Introduction: lysosomes and lysosomal biology
Since the discovery of lysosome (Appelmans et al., 1955; de Duve, 1983), major efforts have been done to understand its biology and multitude functions. Lysosomes are ubiquitous sphere or tubular shape organelles. Their size, abundance and distribution are dependent on the digestive activity and cell type (Xu and Ren, 2015). Lysosomal membrane, which was long thought to serve primarily as the physical barrier to prevent mixing of the highly acidic lumen with cytosol, is known to have a number of other important functions, which are largely associated with the numerous membrane proteins transporters, receptors and enzymes, anchored into the lysosomal membrane. Lysosomal integral membrane proteins (LIMPs) and lysosomal associated membrane proteins (LAMPs) are protected against the attack of proteases by heavy glycosylation, which forms gylcocalyx. Membrane is additionally stabilised by heat shock protein 70 kDa (Hsp70) and cholesterol (Saftig et al., 2010; Repnik et al., 2012; Galluzzi et al., 2014; Mrschtik and Ryan, 2015).
Lysosomes are the terminal point of intracellular transport, particularly endocytosis, phagocytosis and autophagy. During endocytosis the substrates are first enclosed into the early endosomes, which mature into the late endosomes that finally fuse with lysosomes, resulting in digestion of the engulfed material. However, endocytosis is not only related to degradation by lysosomes, but it is also implicated into recycling of surface receptors and cellular signalling (Sigismund et al., 2012; Settembre et al., 2013; Xu and Ren, 2015). During autophagy, the engulfed contents are transported from the cytoplasm to the lysosomes for final degradation (Ciechanover, 2012; Kaur and Debnath, 2015). According to the physiological activity and the type of cargo distribution to the lysosomes three distinct autophagy pathways are known: macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). Macroautophagy, an evolutionary conserved process, is present at a low level (constitutive autophagy) in all cells to preserve intracellular balance and is stimulated during stress conditions, like starvation, imbalance in AMP/ATP ratio, reactive oxygen species stress, endoplasmic reticulum stress and accumulated misfolded proteins. CMA is activated as protection system to avoid proteotoxicity. All CMA substrates contain in the sequence a specific pentapeptide motif (e.g. KFERQ) that serves for binding to the chaperone proteins shock cognate protein 70 (Hsc70), and is delivered to lysosomes via LAMP-2A protein that serves as a receptor (Mizushima et al., 2008; Arias and Cuervo, 2011; Cuervo and Wong, 2014). Microautophagy is the least investigated mechanism, during which the lysosomal membrane is invaginated thereby trapping its content. This pathway was shown to be involved in the clearance of large structures, like mitochondria and peroxisomes. The engulfed membrane is degraded to release the cytoplasmic cargo (Li et al., 2012).
When the cargo finally reaches the lysosome, the delivered content is modified by acidic pH and reducing environment resulting in reduction of the disulphide bonds, disruption of the hydrogen bonds and the connexions between the side chains leading to unfolding of the proteins (Luzio et al., 2000; Turk and Turk, 2009; Cesen et al., 2012). The acidic pH is maintained by V-ATPase and ion homeostasis that are essential for lysosomal maturation and trafficking, proper membrane fission and establishment of the lysosomal membrane potential (Xu and Ren, 2015).
The improper function of autophagy and decreased lysosomal degradation may result in accumulation of lipofuscin (age pigment), an auto-fluorescent material, in lysosomes of post-mitotic long-lived cells (Terman and Brunk, 2004; Hohn and Grune, 2013). Lipofuscin is composed of peroxidised proteins and lipid residues, which may act as endogenous membranolytic compounds. Additionally, some studies have revealed that some metals like aluminium, zinc, copper and iron are trapped within lipofuscin. Among them iron has a special role as it is predominantly responsible for oxidation linked with the Fenton-type reactions, indicating that lysosomes are also involved in iron homeostasis (Kurz et al., 2007; Kurz et al., 2011; Hohn and Grune, 2013; Karlsson et al., 2013; Repnik et al., 2014; Bogdan et al., 2016). However, lysosomes are not associated only with the catabolic functions, but also with other processes, including cell death, inflammasome activation and immune response, as well as with lysosomal secretion and cholesterol recycling (Appelqvist et al., 2013; Mrschtik and Ryan, 2015). As a consequence, disturbances in lysosomal functions are associated with numerous human diseases, such as cancer, neurodegenerative disorders, lysosomal storage diseases, cardiovascular disorders and many inflammation-associated diseases (Eskelinen and Saftig, 2009; Kurz et al., 2011; Appelqvist et al., 2013; Settembre et al., 2013; Jiang and Mizushima, 2014; Hu et al., 2015; Parenti et al., 2015; Bogdan et al., 2016; Stoka et al., 2016).
Lysosomal hydrolases: crucial role of proteases
Crucial role in cargo degradation play lysosomal hydrolases. A number of them has been identified in the lysosomal lumen, including proteases, nucleases, lipases, phosphatases, sulfatases and glycosidases (Hafner Cesen et al., 2016). Their function is to hydrolyse the incoming cargo into simple building blocks, which are reused after diffusion or active transport by catabolite exporters into the cytosol (Mrschtik and Ryan, 2015; Xu and Ren, 2015).
Among the hydrolases the best characterised are the proteases, in particular the cathepsins. The majority of them is cysteine cathepsins with 11 of them being encoded in the human genome (B, C, F, H, L, K, O, S, V, W, and X). While cathepsins B, C, F, H, L, O, V and X are ubiquitous and are associated with general lysosomal protein degradation, cathepsins K (osteoclasts), W (lymphocytes and natural killer cells) and S (antigen-presenting cells) are tissue-specific with more specialised functions. Cathepsins D and E are aspartic proteases, ubiquitous in late endosomes, while serine protease G is not classified as a true lysosomal protease, because it is present only in azurophil granules, which belong to the group of lysosome-related organelle (LRO), and is normally active at neutral pH. The most abundant are cathepsins B, L and D, and their inhibition was found to substantially reduce autophagy. Acidic pH found in lysosomes does not only help in unfolding the protein substrates, but is also optimal for the activity of cysteine and aspartic cathepsins. Although active, the former are, with exception of cathepsin S, unstable at neutral pH, while the latter are largely inactive due to reversible deprotonation of the active site Asp residues. Besides pH, a number of other cellular mechanisms are known to prevent uncontrolled proteolytic degradation, including by physical separation of the proteases by being contained within lysosomes, requirement for activation of inactive zymogens and the presence of endogenous inhibitors. However, when regulation fails, cathepsins have been found to be involved in numerous pathologies, especially those associated with inflammation, such as arthritis, atherosclerosis, inflammatory bowel diseases and various autoimmune diseases, as well as several types of cancer. In a number of these conditions, cathepsins were found to be upregulated and often also secreted (Turk et al., 2001; Vasiljeva et al., 2007; Kaminskyy and Zhivotovsky, 2012; Turk et al., 2012). In addition, there is increasing evidence that cathepsins when released into the cytosol following lysosomal membrane permeabilization, also contribute to various cell death pathways, thereby playing a dual role (Vasiljeva and Turk, 2008).
In this review, we will focus on the lysosomal membrane permeabilization and its triggers. In addition, involvement of lysosomes and lysosomal proteases in various types of regulated cell death pathways will be discussed.
Lysosomal membrane permeabilization and lysosomotropic reagents
A major step in all cell death pathways associated with lysosomes is the lysosomal membrane permeabilization (LMP) that is characterised by decreased cytosolic and increased lysosomal pH, perturbed iron homeostasis, defects in lysosomal cytoprotective factors and release of hydrolases into the cytosol (Figure 1). However, LMP is not always accompanied by ultrastructural changes of lysosomes (Cesen et al., 2012; Aits and Jaattela, 2013; Galluzzi et al., 2014). LMP is dependent on the type of the lysosomotropic agent, presence and activity of the lysosomal enzymes, composition of the lysosomal membrane (e.g. cholesterol and sphingolipid ratio) and the level of endocytosis. In addition, it was suggested that not all cells are equally prone to LMP due to the presence of different enzymes at different levels and that this may also differ depending on the LMP-trigger. So far, an essential role of LMP was demonstrated only in the execution of lysosomal cell death (LCD). LMP was often found to accompany other types of cell death as a downstream signal amplifier, but not as a starting event (Galluzzi et al., 2014; Repnik et al., 2014; Gomez-Sintes et al., 2016; Serrano-Puebla and Boya, 2016). Anyhow, in oxidative stress-triggered necrosis, LMP was found to be an early event (Vanden Berghe et al., 2010). In addition, lysosomal malfunction as a consequence of LMP is also contributing to autophagy defects (Galluzzi et al., 2014; Serrano-Puebla and Boya, 2016). Interestingly, cells were able to recover from moderate LMP through a selective form of autophagy termed lysophagy, in which damaged lysosomes are recovered (Hung et al., 2013; Maejima et al., 2013).
Collectively, it is now clear that LMP is tightly associated with cell death, but the molecular mechanisms downstream of LMP differ and depend on the LMP trigger and cell type (Turk and Turk, 2009; Repnik et al., 2012; Aits and Jaattela, 2013; Ashoor et al., 2013).
Disruption of lysosomal morphology and activity can be a consequence of osmotic or direct membrane lysis (Repnik et al., 2014; Villamil Giraldo et al., 2014). In the case of osmotic lysis, a relatively high quantity of soluble compounds is trapped in the lumen, thereby increasing the osmotic pressure. On the other hand, increased osmotic pressure can be also triggered by the reagents that affect membrane permeability, resulting in the influx of water. Other destabilising factors are compounds with surfactant properties. After the critical micelle concentration is reached, these reagents evolve detergent-like activity (Gomez-Sintes et al., 2016).
To induce membranolytic activity, high concentrations of exogenous lysosomotropic detergents must be used to destabilise intracellular membranes and not only the plasmalemma. Among these compounds the most important are the lysosomotropic compounds (Figure 1). Lysosomotropic compounds are usually weak basis that upon entering lysosomes become protonated at acidic pH, thereby remaining trapped within lysosomes. However, they often affect lysosomal pH only, but do not trigger LMP. Such examples are chloroquine and ammonium chloride, which exert the so-called “sponge effect” by accumulating in the lysosomes due to protonation at acidic pH thereby increasing the vesicles volume and pH. The latter is, however, seen as a decrease in the signal of lysosomotropic dyes such as acridine orange and various lysotrackers and therefore sometimes misinterpreted as LMP, requiring caution in data interpretation (Repnik et al., 2014). Another such example is siramisine, a σ2-receptor agonist, which was initially reported to trigger LMP and subsequent cell death in several cancer cells (Ostenfeld et al., 2005; Ostenfeld et al., 2008), but was recently found to induce cell death associated with mitochondrial destabilisation and disrupted metabolic homeostasis in the absence of LMP (Cesen et al., 2013).
On the other hand, lysosomotropic detergents destabilise membrane lipids after delivery into the lysosome. Early examples of lysosomotropic detergents were amines with hydrophobic side-chains, such as imidazole or morpholine (Miller et al., 1983), although it is not completely clear whether they disrupt lysosomal membranes only or also plasmalemma, and whether this is cell type-dependent. However, the best characterised lysosomotropic detergent is L-leucyl-L-leucine methyl ester (LeuLeuOMe), which can kill a large variety of cells with bone marrow-derived immune cells being the most sensitive (Thiele and Lipsky, 1990; Uchimoto et al., 1999; Droga-Mazovec et al., 2008). This dipeptide ester was shown to accumulate inside lysosomes and acquired detergent properties after polymerization mediated by cathepsin C (Thiele and Lipsky, 1990). Moreover, the compound showed excellent results in the prevention of graft-versus-host disease in mice and entered clinical studies for allogenic bone marrow transplantation (Filicko-O’Hara et al., 2009), which were, however, discontinued. Among the others, O-methyl-serine-dodecylamide-hydrochloride (MSDH) and sphingosine have gained more attention. MSDH was thus shown to trigger early LMP accompanied by leakage of lysosomal proteases, changed iron homeostasis and oxidative stress, followed by release of cytochrome C from mitochondria and activation of caspases at low to moderate concentrations in a mouse macrophage cell line. However, high doses of MSDH resulted in necrosis of the target cells (Li et al., 2000; Ghosh et al., 2011). Sphingosine, on the other hand, is one of the endogenous lysosomotropic agents, which causes changes in lysosomal membrane lipid composition. Sphingosine is generated by concerted action of acid sphingomyelinase and acid ceramide. While the former converts sphingomyelin into ceramide, the latter converts ceramide into sphingosine. Another important factor in the sphingosine detergent activity seems to be also cathepsin B, which degrades sphingosine into the anti-apoptotic sphingosine 1-phosphate. In addition, sphingosine membranolytic properties depend on pH and lipid composition (Johansson et al., 2010; Young et al., 2013; Villamil Giraldo et al., 2014). In addition, destabilisation of lysosomal membrane can be mediated also by non-permeable compounds that accumulate in lysosomes after delivery by endocytosis (Aits and Jaattela, 2013; Repnik et al., 2014; Villamil Giraldo et al., 2014).
ROS as LMP trigger
A potent intracellular LMP inducer, following exposure to various drugs, heavy metals, ionising radiation, photodynamic therapy and different injuries, is also oxidative stress (Figure 1A) (Cesen et al., 2012; Aits and Jaattela, 2013). In the lysosome, low mass-iron is released after degradation of ferruginous compounds. During increased oxidative stress H2O2 enters into the lysosomes and reacts with redox-active iron in Fenton-type reaction (Fe2+ + H2O2 → Fe3+ + OH˙ + OH−). Alternatively, O2˙− presence leads to reduction of iron and occurrence of harmful hydroxyl radical OH˙. Further, the ferric cation Fe3+ formed in the Fenton reaction can react with the superoxide anion in the so-called Haber-Weiss reaction, generating ferrous iron again (Fe3+ + O2˙− → Fe2+ + O2), which can re-enter into the Fenton reaction (Kurz et al., 2007; Kurz et al., 2011; Dixon et al., 2012). Depending on the extent of highly reactive HO. and OH− production, LMP is triggered by lipid peroxidation and destabilisation of lysosomal membrane proteins. It was suggested that ROS initiate also activation of phospholipase A2 (PLA2) and lysosomal Ca2+ channels. PLA2 may affect trafficking of K+ and H+ ions and lysosomal membrane integrity by the production of arachidonic acid, which exhibits detergent-like properties (Kurz et al., 2011; Cesen et al., 2012; Aits and Jaattela, 2013).
However, not all lysosomes are equally sensitive to oxidative stress due to variation in the degradation level of the iron-binding molecules. Consistent with this theory, the level of lysosomal redox-active iron in healthy cells should be strictly regulated by transporting iron from lysosomes to cytosol and keeping it in a non-redox-active form. Hsp70 and ferritin can bind iron in order to diminish LMP. Therefore, many efforts were invested in the introduction of redox-active iron in malignant cells to be more responsive to irradiation-induced ROS production. In addition, anti-cancer photodynamic therapy is based on the intra-lysosomal accumulation of photosensitizers that cause increased oxidative stress resulting in LMP, release of lysosomal hydrolases and mitochondrial membrane permeabilization (MMP) (Kurz et al., 2007, 2011; Ghosh et al., 2011; Marino et al., 2013).
In the cell, excessive ROS act as general destabilising factors, but cellular antioxidants can minimise their impact. Lysosomal integrity can be maintained by vitamins C and E, coenzyme Q10, glutathione, catalase, superoxide dismutase, etc. However, their anti-oxidative properties can be diminished by the low lysosomal pH (Johansson et al., 2010; Kurz et al., 2011; Aits and Jaattela, 2013; Marino et al., 2013; Bogdan et al., 2016).
An interesting group of biomolecules that can trigger LMP are bacterial, fungal and snake toxins, and viral proteins. Perhaps the best known example is the diphtheria toxin, which forms pores in endolysosomal membranes after pH modification. Also several other toxins, such as tetanus, botulinum an anthrax toxin, nigericin, leukotoxin, mycotoxins, venom toxins from cobra and rattlesnake, have been associated with LMP. On the other hand, viral proteins can initiate LMP by generating lysosomal membrane rupture, pore formation, membrane curvature stress or vesicular swelling or even by detergent-like activity (Tosteson and Chow, 1997; Fuchs and Blaas, 2010; Johansson et al., 2010; Maier et al., 2010; Aits and Jaattela, 2013; Jiang and Mizushima, 2014; Ju et al., 2015). In addition, proapoptotic Bcl2 family members Bax and Bak that are primarily involved in mitochondrial membrane permeabilization, and Bid, were also suggested to be involved in triggering LMP (Johansson et al., 2010).
Lysosomes in cell death
Following LMP, lysosomes start leaking their contents into the cytosol, which may lead to cell death. Unlike the pathways leading to LMP, pathways downstream from LMP are clearer and are critically dependent on the release of lysosomal hydrolases into the cytosol. Although their activity in the cytosol is lower than in the endolysosomal vesicles, it can still result in substantial damage, depending on the extent of LMP and cytosolic (protease) inhibitors, which can protect cells against low level LMP, thereby serving an emergency role (Turk, 2006), such as demonstrated for stefin B. Its genetic ablation was namely shown to dramatically sensitise primary mouse mammary cancer cells to LeuLeuOMe (Butinar et al., 2014). Extensive LMP leads to uncontrolled necrosis, which will not be discussed further, while moderate LMP contributes to apoptosis and various types of regulated necrosis, including necroptosis, ferroptosis, oxytosis, pyrogenic cell death, cornification and parthanatos (Figure 2) (Turk and Turk, 2009; Cesen et al., 2012; Lima et al., 2013; Galluzzi et al., 2014; Vanden Berghe et al., 2014). Like in apoptosis also in regulated necrosis LMP can be an initiator, an amplifier or only a bystander of the process. Moreover, lysosomes do not contribute to regulated necrosis only by the activity of released cathepsins but also by their elevated oxidative potential and iron load (Figure 3) (Vanden Berghe et al., 2010; Galluzzi et al., 2014). A comparison between different types of cell death is presented in Table 1.
Depending on the initial signal, apoptosis can be driven by mitochondria (intrinsic pathway) or by ligation of death ligands to transmembrane receptors from the TNF family (extrinsic pathway), which both converge at the level of caspase 3 activation. The two pathways are connected via the BH3-only proapoptotic Bcl-2 family member Bid, which is a substrate of caspase 8. Such truncated form of Bid, tBid, then engages the mitochondrial pathway in the so-called type I cells, thereby amplifying the signal. LMP somehow does not fit into the main story. The early idea that cathepsins released from the lysosomes would activate procaspases, as shown in vitro for cathepsin G (Zhou and Salvesen, 1997), does not work (Stoka et al., 2001). The only exception is cathepsin D, which was shown to be able to activate procaspase 8 in neutrophils (Conus et al., 2008). However, this is more an exception than a rule, as cathepsin D is extremely abundant in neutrophils. Moreover, there is no endogenous inhibitor of cathepsin D in mammals, suggesting lower level of control.
The first identified substrate of cathepsins, including cathepsin D, leading to apoptosis is Bid. Similarly to caspase 8 and granzyme B, all the cathepsins cleave Bid in the same unstructured region, called the bait loop (Stoka et al., 2001; Cirman et al., 2004; Heinrich et al., 2004; Blomgran et al., 2007; Droga-Mazovec et al., 2008). However, Bid is not a critical apoptotic substrate of cathepsins as demonstrated in neuronal apoptosis in mice deficient in the major cytosolic inhibitor of cysteine cathepsins. Simultaneous ablation of stefin B and Bid had namely no effect on the progression of cerebellar apoptosis (Houseweart et al., 2003). Later, several additional apoptotic substrates of cathepsins were identified, including the anti-apoptotic Bcl2 family proteins Bcl-2, Bcl-extra-large (Bcl-XL) and induced myeloid leukaemia cell differentiation protein-1 (Mcl-1). This all points out to engagement of mitochondrial pathway. Moreover, cathepsins can also cleave XIAP following its release from mitochondria, thereby ensuring the propagation of apoptosis (Droga-Mazovec et al., 2008). The importance of cathepsins for triggering LMP-mediated cell death was demonstrated also in primary tumour cells, which were genetically ablated for cathepsin B or the major cytosolic cathepsin inhibitor stefin B (Vasiljeva et al., 2008; Butinar et al., 2014). While triggering LMP by lysosomotropic detergents seems an attractive alternative to kill cancer or immune cells overexpressing anti-apoptotic Bcl2 proteins in cancer therapy, LMP does not seem to be a major apoptotic pathway. However, since mitochondrial membrane permeabilization (MMP) results also in oxidative stress, which may trigger LMP, it can be suggested that secondary LMP may amplify apoptosis. Of course, this is probably true also for other LMP stimuli. There were some more controversies concerning the role of LMP in the extrinsic pathway, suggesting that cathepsins, in particular cathepsin B, may act as important direct executioners of apoptosis (Guicciardi et al., 2004; Kirkegaard and Jaattela, 2009). However, later studies revealed that cathepsins are not the main players (Bojic et al., 2007; Wattiaux et al., 2007; Vasiljeva et al., 2008; Oberle et al., 2010; Spes et al., 2012). In addition, LMP was often linked to neuronal cell death, where pathways may be somewhat different than in other cells described above. Since the role of lysosomes and LMP in apoptosis was a subject of many reviews, it will not be discussed her in more details (Turk and Turk, 2009; Cesen et al., 2012; Aits and Jaattela, 2013; Repnik et al., 2014; Stoka et al., 2016; Yu et al., 2016).
The most studied form of regulated necrosis is necroptosis, which relies on the activation of receptor interacting protein kinases (RIPK) 1 and 3. Many inducers of necroptosis have been identified so far, however, the tumour necrosis factor (TNF)-induced pathway in the absence of active caspase 8, which otherwise cleaves the two kinases and drives cells into apoptosis, is the most studied one (Pasparakis and Vandenabeele, 2015). In contrast to accidental necrosis where LMP is an early event, in TNF-induced necroptosis LMP occurs at a later stage (Vanden Berghe et al., 2010). In a recent study, cysteine cathepsins B and S, and to a minor extent also cathepsin L, have been demonstrated to cleave RIPK1 in macrophages and only the combined inhibition of caspases and cathepsins has augmented TNF-necroptosis (McComb et al., 2014). In another study, dendritic cells treated with the RIG-I-like receptor adjuvant polyinosinic-polycytidlic acid (poly IC) also showed disrupted lysosomal integrity and cathepsins release. Interestingly, in the majority of the cell population, released cathepsin D acted pro-inflammatory by cleaving caspase-8 which resulted in enhanced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated production of cytokines. However, in a minor portion of the cell population cathepsin D cleavage of caspase-8 resulted in RIPK1-dependent cell death. As only the inhibition of all cathepsins, and not only cathepsin D or cysteine cathepsins, reduced necroptosis, the authors speculated that other lysosomal cathepsins besides cathepsin D may be involved in facilitating poly IC-stimulated necroptosis (Zou et al., 2013).
Based on the available data, it is difficult to conclude if cathepsins promote or delay necroptosis. Most probably, the function of LMP and cathepsins depends on the type of cells and their local microenvironment. It is known that depending on the molecular momentum pro-apoptotic factors can antagonise necroptosis (Ofengeim and Yuan, 2013; Hernandez et al., 2015). In other forms of regulated necrosis described below, LMP and cathepsins seem to contribute to cell death rather than to limit it.
Ferroptosis and oxytosis
Ferroptosis occurs due to erastin inhibition of the XC- cysteine/glutamine antiporter causing cysteine and consequently glutathione depletion. This allows an increase in Fenton generated ROS and subsequently major lipid damage. The critical factor in ferroptosis is most likely antioxidant insufficiency (Dixon et al., 2012; Dixon and Stockwell, 2014). As described above, lysosomes are important cellular pools of redox-active iron and their biochemistry creates an excellent environment for Fenton reactions (Kurz et al., 2011). Interestingly, not all triggers that initiate Fenton reactions in lysosomes cause ferroptosis (Dixon et al., 2012). This further suggests that iron-catalysed ROS from lysosomes are dispensable drivers of ferroptosis (Dixon and Stockwell, 2014). In addition, it was shown that ferroptosis was not affected by the broad spectrum cysteine cathepsin inhibitor E64d implying that lysosomal cysteine cathepsins are neither critical for ferroptotic cell death (Dixon et al., 2012). It can be therefore suggested that lysosomes have a supportive rather than an essential role in ferroptosis.
Oxytosis was initially described as oxidative glutamate-induced death of neuronal cells (Tan et al., 2001; Dixon and Stockwell, 2014). Similar to ferroptosis, oxytosis also relies on the prevention of cysteine uptake by the XC-cysteine/glutamine antiporter. However, in oxytosis this is achieved by cysteine depletion or glutamate saturation. Furthermore, like in ferroptosis also in oxytosis ROS damage membrane lipids. However, this is not sufficient for killing the cell and additional stimuli, such as calcium influx from the extracellular space, which results in activation of calpains, are required (Henke et al., 2013). Since calpains have been previously suggested to be involved in triggering LMP (Yamashima, 2004), this could provide a link between LMP and oxytosis. However, glutamate treatment of mouse hippocampal HT22 cells triggered lysosomal ROS production and cell death but not LMP (Kubota et al., 2010), suggesting a supporting rather than an essential role of lysosomes in oxytosis.
Pyroptosis was discovered as a special form of lytic cell death, induced by microbial infection that is accompanied by the release of proinflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18). Together with necroptosis it has been recently classified as a form of programmed necrosis, where a major role is played by the proinflammatory caspases 1 and 11 in mouse, while in humans the latter is replaced by caspases 4 and 5 (Cookson and Brennan, 2001; Averette et al., 2009; Lamkanfi and Dixit, 2014; Wallach et al., 2016). The process is started by the activation of intracellular nucleotide oligomerisation domain-like recognition receptors (NLRs) that form the inflammasome together with the apoptosis-associated speck-like protein containing a CARD (ASC), which enable pro-caspase 1 activation. In such way, the inflammasome promotes maturation of the pyrogenic IL-1β and IL-18 cytokines that are secreted from cells. A major role in the process also plays the caspase 11 substrate gasdermin D (GSDMD), which was found to be critical for non-canonical inflammasome signalling by Gramme-negative bacteria and subsequent pyroptosis, as well as for activation of IL-1β (Guo et al., 2015; Kayagaki et al., 2015). In addition, recent findings have provided evidence that the N-terminal domains of GSDMD and other gasdermin proteins (GSDMA and GSDMA3) are involved in pyroptotic pore formation. These pore-forming proteins can affect either plasmalemma or peroxisome and mitochondrial membranes (Ding et al., 2016; Sborgi et al., 2016).
There is also increasing evidence that inflammasome activation triggered by different stimuli, including bacterial toxins, silica crystals, aluminium salts, lipofuscin and lysosomotropic detergent LeuLeuOMe (Hornung et al., 2008; Duewell et al., 2010; Tseng et al., 2013), cholesterol crystals (Duewell et al., 2010), and mitochondrial ROS (Heid et al., 2013) is accompanied by LMP. For example, Bacillus anthracis lethal toxin (LT) triggers NLRs and also induces LMP in macrophages, which results in pyroptotic cell death. Moreover, active cathepsins were found in the cytosol of LT-treated macrophages and their inhibition prevented LT-induced pyroptosis, suggesting that a moderate LMP could contribute to inflammasome activation (Averette et al., 2009). In addition, it has been demonstrated that the cathepsin B-selective inhibitor CA-074-Me, but not cathepsin B deficiency, effectively blocked pyroptosis and IL-1β release mediated by silica (Hornung et al., 2008; Tseng et al., 2013). However, it still unclear if cathepsins induce inflammasome activation directly or indirectly through a yet unidentified signalling pathway (Hornung et al., 2008; Averette et al., 2009; Newman et al., 2009; Lima et al., 2013).
Surprisingly, in the study of Lima et al. (Lima et al., 2013) early lysosomal rupture by LeuLeuOMe and alum in macrophages resulted in necrotic cell death independent of the inflammasome-activated caspase-1. The authors observed that LMP resulted in a range of opposing cellular responses, from a broad degradation of cellular proteins, including caspase-1, IL-1β, and IL-18, to a minor activation of pro-caspase-1 and pro-IL-1β. Importantly, activation of caspase-1 did not depend on the inflammasome activation. The authors named this pyrogenic cell death lysosome-mediated necrosis. They further observed that the release of IL-1β was still dependent on caspase-1 processing, whereas the final cell death was not (Lima et al., 2013). Similar to pyroptosis, also LeuLeuOMe-mediated necrosis and IL-1β maturation could be attenuated by CA-074-Me, but not by genetic ablation of cathepsin B, in agreement with the lower specificity of the methylated form of the inhibitor. LeuLeuOMe-triggered cell death in monocytes, dendritic cells and neutrophils, but not pyroptosis, could be also prevented by ablation of cathepsin C. Furthermore, downregulation of the aspartic cathepsin D in macrophages also blocked LeuLeuOMe necrosis, suggesting a link between cathepsin D and cathepsin C activation in lysosome-mediated necrosis (Lima et al., 2013; Brojatsch et al., 2015). However, at least in vitro studies do not support the role of cathepsin D in cathepsin C activation (Dahl et al., 2001).
Another caspase-1-independent form of cell death named pyronecrosis has been described in response to Shigella flexneri and Neisseria gonorrhoeae infection. Also in these cases, inhibition of cathepsin B, and possibly other proteases, by CA-074-Me attenuated cell death and limited inflammatory cytokine release (Willingham et al., 2007; Duncan et al., 2009). This further suggests that inducers of pyrogenic cell death, including lysosome-destabilising agents, trigger different cellular events, which importantly rely on the extent and timing of LMP.
Cornification is a distinct type of programmed cell death of epidermal cells, closely related to skin layers’ formation. Corneocytes – dead keratinocytes – become part of the outer skin barrier, fundamental for protection against mechanical, chemical or biological stressors. During this 2-weeks long cellular transformation, various enzymes become involved in organelle degradation, such as proteases, nucleases, and transglutaminases (Lippens et al., 2009; Eckhart et al., 2013). After degradation, free areas within the cell are replaced by cytoskeleton and a cornified cell envelope is created at the intracellular edges of the cell. In spite of many studies about cornification, the exact role of lysosomal proteases and LMP remains unclear, although cathepsins V and L and legumain have been detected in the cytosol of keratinocytes. One of the crucial regulators of cornification seems to be the cysteine protease inhibitor cystatin M/E, which inhibits legumain and cathepsins V and L (Zeeuwen et al., 2009). Its genetic ablation resulted in mice dying shortly after birth due to disturbed cornification, impaired barrier function and consequent dehydration (Zeeuwen et al., 2002). The critical cystatin E/M target seems to be cathepsin L/V, as simultaneous ablation of cathepsin L rescued cystatin E/M deficient mice lethality (Zeeuwen et al., 2010). Based on the deletion of cystatin E/M in a reconstructed human skin model, which showed an impaired epidermis development instead of ichthyosis-like features, it was suggested that the inhibitor might be critical also for humans (Jansen et al., 2012). Moreover, the transglutaminase activity is also dependent on release of cathepsins from lysosomes and Ca2+ from endoplasmic reticulum and thereby on cystatin E/M cathepsin L/V axis. However, calpain-1-dependent LMP, which is triggered after tight envelope formation to prevent uncontrolled degradation, occurs from unknown reason (Zeeuwen et al., 2009; Eckhart et al., 2013; Costanzo et al., 2015). Anyhow, dysregulation of proteases and their inhibitors in the skin might be related to development of various diseases, such as Netherton syndrome, Papillon-Lefevre syndrome as well as impaired skin barrier function (Zeeuwen, 2004; Cheng et al., 2009; Zeeuwen et al., 2009; Jansen et al., 2012).
Poly (ADP-ribose)-polymerase 1 (PARP1), also known as NAD+ ADP-ribosyltransferase, is mostly recognised for being engaged in DNA repair. However, hyperactivation of PARP1 leads to regulated necrotic cell death termed parthanatos. PARP1 is a target of many enzymes, among them apoptotic caspases, granzymes and cathepsins. The production of variety of different PARP1 fragments could mediate specific forms of cell death. For example, after LMP cathepsins B, D and G can cleave PARP1 into 44 kDa, 55 kDa, 62 kDa, 74 kDa and 89 kDa necrotic fragments, which might contribute to cell death, although the molecular mechanisms behind this are not completely clear yet. However, due to the complexity and diversity of cleaved PARP1 fragments it is difficult to associate them to a specific PARP1-controlled process including parthanatos (Chaitanya et al., 2010; Galluzzi et al., 2014).
Lysosomes and LMP have been often connected with different types of cell death. While their major role in necrosis and autophagy/autophagic cell death is clear, their role in programmed cell death pathways seems to be more restricted to amplification of the different pathways, rather than to their initiation. The only real exception is apoptosis triggered by lysosomotropics, however, this is not really a physiological pathway. Nevertheless, use of lysosomotropics may be beneficial at least as supportive therapy in several diseases, including cancer. However, additional studies are needed, before we will really understand this complex organelle and its role in general, not only in cell death.
This work was supported by grant P1-0140 from Slovenian Research Agency to B.T.
Aits, S. and Jaattela, M. (2013). Lysosomal cell death at a glance. J. Cell Sci. 126, 1905–1912. Google Scholar
Appelmans, F., Wattiaux, R., and de Duve, D. (1955). Tissue fractionation studies. 5. The association of acid phosphatase with a special class of cytoplasmic granules in rat liver. Biochem. J. 59, 438–445. Google Scholar
Ashoor, R., Yafawi, R., Jessen, B., and Lu, S. (2013). The contribution of lysosomotropism to autophagy perturbation. PLoS One 8, e82481. Google Scholar
Averette, K.M., Pratt, M.R., Yang, Y., Bassilian, S., Whitelegge, J.P., Loo, J.A., Muir, T.W., and Bradley, K.A. (2009). Anthrax lethal toxin induced lysosomal membrane permeabilization and cytosolic cathepsin release is Nlrp1b/Nalp1b-dependent. PLoS One 4, e7913. Google Scholar
Blomgran, R., Zheng, L., and Stendahl, O. (2007). Cathepsin-cleaved Bid promotes apoptosis in human neutrophils via oxidative stress-induced lysosomal membrane permeabilization. J. Leukoc. Biol. 81, 1213–1223. Google Scholar
Bogdan, A.R., Miyazawa, M., Hashimoto, K., and Tsuji, Y. (2016). Regulators of iron homeostasis: new players in metabolism, cell death, and disease. Trends Biochem. Sci. 41, 274–286. CrossrefGoogle Scholar
Bojic, L., Petelin, A., Stoka, V., Reinheckel, T., Peters, C., Turk, V., and Turk, B. (2007). Cysteine cathepsins are not involved in Fas/CD95 signalling in primary skin fibroblasts. FEBS Lett. 581, 5185–5190. Google Scholar
Brojatsch, J., Lima, H., Jr., Palliser, D., Jacobson, L.S., Muehlbauer, S.M., Furtado, R., Goldman, D.L., Lisanti, M.P., and Chandran, K. (2015). Distinct cathepsins control necrotic cell death mediated by pyroptosis inducers and lysosome-destabilizing agents. Cell Cycle 14, 964–972. CrossrefGoogle Scholar
Butinar, M., Prebanda, M.T., Rajkovic, J., Jeric, B., Stoka, V., Peters, C., Reinheckel, T., Kruger, A., Turk, V., Turk, B., et al. (2014). Stefin B deficiency reduces tumor growth via sensitization of tumor cells to oxidative stress in a breast cancer model. Oncogene 33, 3392–3400. CrossrefGoogle Scholar
Cesen, M.H., Pegan, K., Spes, A., and Turk, B. (2012). Lysosomal pathways to cell death and their therapeutic applications. Exp. Cell Res. 318, 1245–1251. Google Scholar
Cheng, T., van Vlijmen-Willems, I.M., Hitomi, K., Pasch, M.C., van Erp, P.E., Schalkwijk, J., and Zeeuwen, P.L. (2009). Colocalization of cystatin M/E and its target proteases suggests a role in terminal differentiation of human hair follicle and nail. J. Invest. Dermatol. 129, 1232–1242. Google Scholar
Ciechanover, A. (2012). Intracellular protein degradation: from a vague idea thru the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Biochim. Biophys. Acta. 1824, 3–13. Google Scholar
Cirman, T., Oresic, K., Mazovec, G.D., Turk, V., Reed, J.C., Myers, R.M., Salvesen, G.S., and Turk, B. (2004). Selective disruption of lysosomes in HeLa cells triggers apoptosis mediated by cleavage of Bid by multiple papain-like lysosomal cathepsins. J. Biol. Chem. 279, 3578–3587. Google Scholar
Conus, S., Perozzo, R., Reinheckel, T., Peters, C., Scapozza, L., Yousefi, S., and Simon, H.U. (2008). Caspase-8 is activated by cathepsin D initiating neutrophil apoptosis during the resolution of inflammation. J. Exp. Med. 205, 685–698. Google Scholar
Costanzo, A., Fausti, F., Spallone, G., Moretti, F., Narcisi, A., and Botti, E. (2015). Programmed cell death in the skin. Int. J. Dev. Biol. 59, 73–78. Google Scholar
Dahl, S.W., Halkier, T., Lauritzen, C., Dolenc, I., Pedersen, J., Turk, V., and Turk, B. (2001). Human recombinant pro-dipeptidyl peptidase I (cathepsin C) can be activated by cathepsins L and S but not by autocatalytic processing. Biochemistry 40, 1671–1678. CrossrefGoogle Scholar
de Duve, C. (1983). Lysosomes revisited. Eur. J. Biochem. 137, 391–397. Google Scholar
Ding, J., Wang, K., Liu, W., She, Y., Sun, Q., Shi, J., Sun, H., Wang, D.C., and Shao, F. (2016). Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535, 111–116. Google Scholar
Dixon, S.J., Lemberg, K.M., Lamprecht, M.R., Skouta, R., Zaitsev, E.M., Gleason, C.E., Patel, D.N., Bauer, A.J., Cantley, A.M., Yang, W.S., et al. (2012). Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072. Google Scholar
Droga-Mazovec, G., Bojic, L., Petelin, A., Ivanova, S., Romih, R., Repnik, U., Salvesen, G.S., Stoka, V., Turk, V., and Turk, B. (2008). Cysteine cathepsins trigger caspase-dependent cell death through cleavage of bid and antiapoptotic Bcl-2 homologues. J. Biol. Chem. 283, 19140–19150. Google Scholar
Duewell, P., Kono, H., Rayner, K.J., Sirois, C.M., Vladimer, G., Bauernfeind, F.G., Abela, G.S., Franchi, L., Nunez, G., Schnurr, M., et al. (2010). NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361. Google Scholar
Duncan, J.A., Gao, X., Huang, M.T., O’Connor, B.P., Thomas, C.E., Willingham, S.B., Bergstralh, D.T., Jarvis, G.A., Sparling, P.F., and Ting, J.P. (2009). Neisseria gonorrhoeae activates the proteinase cathepsin B to mediate the signaling activities of the NLRP3 and ASC-containing inflammasome. J. Immunol. 182, 6460–6469. Google Scholar
Eckhart, L., Lippens, S., Tschachler, E., and Declercq, W. (2013). Cell death by cornification. Biochim. Biophys. Acta. 1833, 3471–3480. Google Scholar
Eskelinen, E.L. and Saftig, P. (2009). Autophagy: a lysosomal degradation pathway with a central role in health and disease. Biochim. Biophys. Acta. 1793, 664–673. Google Scholar
Filicko-O’Hara, J., Grosso, D., Flomenberg, P.R., Friedman, T.M., Brunner, J., Drobyski, W., Ferber, A., Kakhniashvili, I., Keever-Taylor, C., Mookerjee, B., et al. (2009). Antiviral responses following L-leucyl-L-leucine methyl esther (LLME)-treated lymphocyte infusions: graft-versus-infection without graft-versus-host disease. Biol. Blood Marrow. Transplant. 15, 1609–1619. CrossrefGoogle Scholar
Ghosh, M., Carlsson, F., Laskar, A., Yuan, X.M., and Li, W. (2011). Lysosomal membrane permeabilization causes oxidative stress and ferritin induction in macrophages. FEBS Lett. 585, 623–629. Google Scholar
Gomez-Sintes, R., Ledesma, M.D., and Boya, P. (2016). Lysosomal cell death mechanisms in aging. Ageing Res. Rev. Google Scholar
Hafner Cesen, M., Stoka, V., and Turk, B. (2016). Role of lysosomes in intracellular degradation. In: Encyclopedia of Cell Biology. Google Scholar
Heid, M.E., Keyel, P.A., Kamga, C., Shiva, S., Watkins, S.C., and Salter, R.D. (2013). Mitochondrial reactive oxygen species induces NLRP3-dependent lysosomal damage and inflammasome activation. J. Immunol. 191, 5230–5238. Google Scholar
Heinrich, M., Neumeyer, J., Jakob, M., Hallas, C., Tchikov, V., Winoto-Morbach, S., Wickel, M., Schneider-Brachert, W., Trauzold, A., Hethke, A., et al. (2004). Cathepsin D links TNF-induced acid sphingomyelinase to Bid-mediated caspase-9 and -3 activation. Cell Death Differ. 11, 550–563. CrossrefGoogle Scholar
Henke, N., Albrecht, P., Bouchachia, I., Ryazantseva, M., Knoll, K., Lewerenz, J., Kaznacheyeva, E., Maher, P., and Methner, A. (2013). The plasma membrane channel ORAI1 mediates detrimental calcium influx caused by endogenous oxidative stress. Cell Death Dis. 4, e470. Google Scholar
Hernandez, L., KIM, M.K., Noonan, A.M., Sagher, E., Kohlhammer, H., Wright, G., Lyle, L.T., Steeg, P.S., Anver, M., Bowtell, D.D., et al. (2015). A dual role for Caspase8 and NF-κB interactions in regulating apoptosis and necroptosis of ovarian cancer, with correlation to patient survival. Cell Death Discovery 1. Google Scholar
Hornung, V., Bauernfeind, F., Halle, A., Samstad, E.O., Kono, H., Rock, K.L., Fitzgerald, K.A., and Latz, E. (2008). Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol. 9, 847–856. CrossrefGoogle Scholar
Houseweart, M.K., Vilaythong, A., Yin, X.M., Turk, B., Noebels, J.L., and Myers, R.M. (2003). Apoptosis caused by cathepsins does not require Bid signaling in an in vivo model of progressive myoclonus epilepsy (EPM1). Cell Death Differ. 10, 1329–1335. Google Scholar
Jansen, P.A., van den Bogaard, E.H., Kersten, F.F., Oostendorp, C., van Vlijmen-Willems, I.M., Oji, V., Traupe, H., Hennies, H.C., Schalkwijk, J., and Zeeuwen, P.L. (2012). Cystatin M/E knockdown by lentiviral delivery of shRNA impairs epidermal morphogenesis of human skin equivalents. Exp. Dermatol. 21, 889–891. CrossrefGoogle Scholar
Johansson, A.C., Appelqvist, H., Nilsson, C., Kagedal, K., Roberg, K., and Ollinger, K. (2010). Regulation of apoptosis-associated lysosomal membrane permeabilization. Apoptosis 15, 527–540. CrossrefGoogle Scholar
Ju, X., Yan, Y., Liu, Q., Li, N., Sheng, M., Zhang, L., Li, X., Liang, Z., Huang, F., Liu, K., et al. (2015). Neuraminidase of influenza A virus binds lysosome-associated membrane proteins directly and induces lysosome rupture. J. Virol. 89, 10347–10358. CrossrefGoogle Scholar
Kaminskyy, V. and Zhivotovsky, B. (2012). Proteases in autophagy. Biochim. Biophys. Acta. 1824, 44–50. Google Scholar
Karlsson, M., Frennesson, C., Gustafsson, T., Brunk, U.T., Nilsson, S.E., and Kurz, T. (2013). Autophagy of iron-binding proteins may contribute to the oxidative stress resistance of ARPE-19 cells. Exp. Eye Res. Google Scholar
Kayagaki, N., Stowe, I.B., Lee, B.L., O’Rourke, K., Anderson, K., Warming, S., Cuellar, T., Haley, B., Roose-Girma, M., Phung, Q.T., et al. (2015). Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671. Google Scholar
Kirkegaard, T. and Jaattela, M. (2009). Lysosomal involvement in cell death and cancer. Biochim. Biophys. Acta. 1793, 746–754. Google Scholar
Kubota, C., Torii, S., Hou, N., Saito, N., Yoshimoto, Y., Imai, H., and Takeuchi, T. (2010). Constitutive reactive oxygen species generation from autophagosome/lysosome in neuronal oxidative toxicity. J. Biol. Chem. 285, 667–674. Google Scholar
Kurz, T., Terman, A., and Brunk, U.T. (2007). Autophagy, ageing and apoptosis: the role of oxidative stress and lysosomal iron. Arch. Biochem. Biophys. 462, 220–230. Google Scholar
Lamkanfi, M. and Dixit, V.M. (2014). Mechanisms and functions of inflammasomes. Cell 157, 1013–1022. Google Scholar
Li, W., Yuan, X., Nordgren, G., Dalen, H., Dubowchik, G.M., Firestone, R.A., and Brunk, U.T. (2000). Induction of cell death by the lysosomotropic detergent MSDH. FEBS Lett. 470, 35–39. Google Scholar
Li, W.W., Li, J., and Bao, J.K. (2012). Microautophagy: lesser-known self-eating. Cell Mol. Life Sci. 69, 1125–1136. Google Scholar
Lima, H., Jr., Jacobson, L.S., Goldberg, M.F., Chandran, K., Diaz-Griffero, F., Lisanti, M.P., and Brojatsch, J. (2013). Role of lysosome rupture in controlling Nlrp3 signaling and necrotic cell death. Cell Cycle 12, 1868–1878. Google Scholar
Luzio, J.P., Rous, B.A., Bright, N.A., Pryor, P.R., Mullock, B.M., and Piper, R.C. (2000). Lysosome-endosome fusion and lysosome biogenesis. J. Cell Sci. 113, 1515–1524. Google Scholar
Maejima, I., Takahashi, A., Omori, H., Kimura, T., Takabatake, Y., Saitoh, T., Yamamoto, A., Hamasaki, M., Noda, T., Isaka, Y., et al. (2013). Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. EMBO J. 32, 2336–2347. CrossrefGoogle Scholar
Maier, O., Galan, D.L., Wodrich, H., and Wiethoff, C.M. (2010). An N-terminal domain of adenovirus protein VI fragments membranes by inducing positive membrane curvature. Virology 402, 11–19. Google Scholar
Marino, J., Garcia Vior, M.C., Furmento, V.A., Blank, V.C., Awruch, J., and Roguin, L.P. (2013). Lysosomal and mitochondrial permeabilization mediates zinc(II) cationic phthalocyanine phototoxicity. Int. J. Biochem. Cell Biol. 45, 2553–2562. CrossrefGoogle Scholar
McComb, S., Shutinoski, B., Thurston, S., Cessford, E., Kumar, K., and Sad, S. (2014). Cathepsins limit macrophage necroptosis through cleavage of Rip1 kinase. J. Immunol. 192, 5671–5678. Google Scholar
Miller, D.K., Griffiths, E., Lenard, J., and Firestone, R.A. (1983). Cell killing by lysosomotropic detergents. J. Cell Biol. 97, 1841–1851. Google Scholar
Mizushima, N., Levine, B., Cuervo, A.M., and Klionsky, D.J. (2008). Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075. Google Scholar
Newman, Z.L., Leppla, S.H., and Moayeri, M. (2009). CA-074Me protection against anthrax lethal toxin. Infect. Immun. 77, 4327–4336. Google Scholar
Oberle, C., Huai, J., Reinheckel, T., Tacke, M., Rassner, M., Ekert, P.G., Buellesbach, J., and Borner, C. (2010). Lysosomal membrane permeabilization and cathepsin release is a Bax/Bak-dependent, amplifying event of apoptosis in fibroblasts and monocytes. Cell Death Differ. 17, 1167–1178. CrossrefGoogle Scholar
Ostenfeld, M.S., Fehrenbacher, N., Hoyer-Hansen, M., Thomsen, C., Farkas, T., and Jaattela, M. (2005). Effective tumor cell death by sigma-2 receptor ligand siramesine involves lysosomal leakage and oxidative stress. Cancer Res. 65, 8975–8983. CrossrefGoogle Scholar
Ostenfeld, M.S., Hoyer-Hansen, M., Bastholm, L., Fehrenbacher, N., Olsen, O.D., Groth-Pedersen, L., Puustinen, P., Kirkegaard-Sorensen, T., Nylandsted, J., Farkas, T., et al. (2008). Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation. Autophagy 4, 487–499. CrossrefGoogle Scholar
Pasparakis, M. and Vandenabeele, P. (2015). Necroptosis and its role in inflammation. Nature 517, 311–320. Google Scholar
Repnik, U., Stoka, V., Turk, V., and Turk, B. (2012). Lysosomes and lysosomal cathepsins in cell death. Biochim. Biophys. Acta. 1824, 22–33. Google Scholar
Sborgi, L., Ruhl, S., Mulvihill, E., Pipercevic, J., Heilig, R., Stahlberg, H., Farady, C.J., Muller, D.J., Broz, P., and Hiller, S. (2016). GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J. 35, 1766–1778. CrossrefGoogle Scholar
Serrano-Puebla, A. and Boya, P. (2016). Lysosomal membrane permeabilization in cell death: new evidence and implications for health and disease. Ann. N Y Acad. Sci. 1371, 30–44. Google Scholar
Settembre, C., Fraldi, A., Medina, D.L., and Ballabio, A. (2013). Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat. Rev. Mol. Cell Biol. 14, 283–296. CrossrefGoogle Scholar
Sigismund, S., Confalonieri, S., Ciliberto, A., Polo, S., Scita, G., and Di Fiore, P.P. (2012). Endocytosis and signaling: cell logistics shape the eukaryotic cell plan. Physiol. Rev. 92, 273–366. CrossrefGoogle Scholar
Spes, A., Sobotic, B., Turk, V., and Turk, B. (2012). Cysteine cathepsins are not critical for TRAIL- and CD95-induced apoptosis in several human cancer cell lines. Biol. Chem. 393, 1417–1431. Google Scholar
Stoka, V., Turk, B., Schendel, S.L., Kim, T.H., Cirman, T., Snipas, S.J., Ellerby, L.M., Bredesen, D., Freeze, H., Abrahamson, M., et al. (2001). Lysosomal protease pathways to apoptosis. Cleavage of bid, not pro-caspases, is the most likely route. J. Biol. Chem. 276, 3149–3157. Google Scholar
Tan, S., Schubert, D., and Maher, P. (2001). Oxytosis: a novel form of programmed cell death. Curr. Top Med. Chem. 1, 497–506. Google Scholar
Thiele, D.L. and Lipsky, P.E. (1990). Mechanism of L-leucyl-L-leucine methyl ester-mediated killing of cytotoxic lymphocytes: dependence on a lysosomal thiol protease, dipeptidyl peptidase I, that is enriched in these cells. Proc. Natl. Acad. Sci. USA 87, 83–87. CrossrefGoogle Scholar
Tosteson, M.T. and Chow, M. (1997). Characterization of the ion channels formed by poliovirus in planar lipid membranes. J. Virol. 71, 507–511. Google Scholar
Tseng, W.A., Thein, T., Kinnunen, K., Lashkari, K., Gregory, M.S., D’Amore, P.A., and Ksander, B.R. (2013). NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 54, 110–120. CrossrefGoogle Scholar
Turk, V., Stoka, V., Vasiljeva, O., Renko, M., Sun, T., Turk, B., and Turk, D. (2012). Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochim. Biophys. Acta. 1824, 68–88. Google Scholar
Uchimoto, T., Nohara, H., Kamehara, R., Iwamura, M., Watanabe, N., and Kobayashi, Y. (1999). Mechanism of apoptosis induced by a lysosomotropic agent, L-Leucyl-L-Leucine methyl ester. Apoptosis 4, 357–362. CrossrefGoogle Scholar
Vanden Berghe, T., Vanlangenakker, N., Parthoens, E., Deckers, W., Devos, M., Festjens, N., Guerin, C.J., Brunk, U.T., Declercq, W., and Vandenabeele, P. (2010). Necroptosis, necrosis and secondary necrosis converge on similar cellular disintegration features. Cell Death Differ. 17, 922–930. CrossrefGoogle Scholar
Vanden Berghe, T., Linkermann, A., Jouan-Lanhouet, S., Walczak, H., and Vandenabeele, P. (2014). Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat. Rev. Mol. Cell Biol. 15, 135–147. CrossrefGoogle Scholar
Vasiljeva, O., Reinheckel, T., Peters, C., Turk, D., Turk, V., and Turk, B. (2007). Emerging roles of cysteine cathepsins in disease and their potential as drug targets. Curr. Pharm. Design 13, 387–403. CrossrefGoogle Scholar
Vasiljeva, O., Korovin, M., Gajda, M., Brodoefel, H., Bojic, L., Kruger, A., Schurigt, U., Sevenich, L., Turk, B., Peters, C., et al. (2008). Reduced tumour cell proliferation and delayed development of high-grade mammary carcinomas in cathepsin B-deficient mice. Oncogene 27, 4191–4199. CrossrefGoogle Scholar
Villamil Giraldo, A.M., Appelqvist, H., Ederth, T., and Ollinger, K. (2014). Lysosomotropic agents: impact on lysosomal membrane permeabilization and cell death. Biochem. Soc. Trans. 42, 1460–1464. CrossrefGoogle Scholar
Wallach, D., Kang, T.B., Dillon, C.P., and Green, D.R. (2016). Programmed necrosis in inflammation: toward identification of the effector molecules. Science 352, aaf2154. Google Scholar
Wattiaux, R., Wattiaux-de Coninck, S., Thirion, J., Gasingirwa, M.C., and Jadot, M. (2007). Lysosomes and Fas-mediated liver cell death. Biochem J 403, 89–95. Google Scholar
Willingham, S.B., Bergstralh, D.T., O’Connor, W., Morrison, A.C., Taxman, D.J., Duncan, J.A., Barnoy, S., Venkatesan, M.M., Flavell, R.A., Deshmukh, M., et al. (2007). Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC. Cell Host. Microbe. 2, 147–159. CrossrefGoogle Scholar
Zeeuwen, P.L. (2004). Epidermal differentiation: the role of proteases and their inhibitors. Eur. J. Cell Biol. 83, 761–773. Google Scholar
Zeeuwen, P.L., van Vlijmen-Willems, I.M., Hendriks, W., Merkx, G.F., and Schalkwijk, J. (2002). A null mutation in the cystatin M/E gene of ichq mice causes juvenile lethality and defects in epidermal cornification. Hum. Mol. Genet. 11, 2867–2875. CrossrefGoogle Scholar
Zeeuwen, P.L., Cheng, T., and Schalkwijk, J. (2009). The biology of cystatin M/E and its cognate target proteases. J. Invest. Dermatol. 129, 1327–1338. Google Scholar
Zeeuwen, P.L., van Vlijmen-Willems, I.M., Cheng, T., Rodijk-Olthuis, D., Hitomi, K., Hara-Nishimura, I., John, S., Smyth, N., Reinheckel, T., Hendriks, W.J., et al. (2010). The cystatin M/E-cathepsin L balance is essential for tissue homeostasis in epidermis, hair follicles, and cornea. FASEB J. 24, 3744–3755. CrossrefGoogle Scholar
Zhou, Q., and Salvesen, G.S. (1997). Activation of pro-caspase-7 by serine proteases includes a non-canonical specificity. Biochem. J. 324, 361–364. Google Scholar
Zou, J., Kawai, T., Tsuchida, T., Kozaki, T., Tanaka, H., Shin, K.S., Kumar, H., and Akira, S. (2013). Poly IC triggers a cathepsin D- and IPS-1-dependent pathway to enhance cytokine production and mediate dendritic cell necroptosis. Immunity 38, 717–728. CrossrefGoogle Scholar
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Published Online: 2016-09-13
Published in Print: 2017-03-01