Abstract
Lipids function as the major building blocks of cellular membranes, as signaling molecules and as energy stores for metabolism. These important functions require a precise regulation of lipid biosynthesis, transport, turnover and storage. Lipids are exchanged among organelles through a sophisticated network of vesicular and non-vesicular transport routes. Lysosomes, as the main catabolic organelle, are at the center of this network and have recently evolved as one of the master-regulators of cellular lipid metabolism. Lipids from both endogenous and exogenous sources can be processed, sensed and sorted in and out of the lysosome. In this review, we focus on the role of the lysosome in lipid catabolism, transport and signaling. We highlight recent discoveries on the transport of lipids out of the lysosomal lumen and their exchange with other organelles via membrane contact sites. We also discuss the direct role of lysosomal lipids in the TORC1 signaling pathway, a regulator of cellular metabolism. Finally, we address lysosomal biogenesis, its role in the sorting of lipid metabolic enzymes and the dysregulation of these processes in disease.
Funding source: Deutsche Forschungsgemeinschaft
Award Identifier / Grant number: SFB944 P20 and P24
Acknowledgment
We thank members of the Fröhlich and González Montoro labs for critical comments on the manuscript.
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Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
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Research funding: This work was funded by DFG (SFB 944, project P20 to F.F., project P24 to A.G.M.).
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Conflict of interest statement: The authors declare no conflicts of interest regarding this article.
References
Adlakha, J., Hong, Z., Li, P., and Reinisch, K.M. (2022). Structural and biochemical insights into lipid transport by VPS13 proteins. J. Cell Biol. 221: e202202030, https://doi.org/10.1083/JCB.202202030/213104.Search in Google Scholar
Alpy, F., Rousseau, A., Schwab, Y., Legueux, F., Stoll, I., Wendling, C., Spiegelhalter, C., Kessler, P., Mathelin, C., Rio, M.C., et al.. (2013). STARD3 or STARD3NL and VAP form a novel molecular tether between late endosomes and the ER. J. Cell Sci. 126: 5500–5512, https://doi.org/10.1242/jcs.139295.Search in Google Scholar PubMed
Altuzar, J., Notbohm, J., Stein, F., Haberkant, P., Heybrock, S., Worsch, J., Saftig, P., and Höglinger, D. (2021). Lysosome-targeted lipid probes reveal sterol transporters NPC1 and LIMP-2 as sphingosine transporters. bioRxiv, https://doi.org/10.1101/2021.11.10.468010.Search in Google Scholar
Balboa, E., Marín, T., Oyarzún, J.E., Contreras, P.S., Hardt, R., van den Bosch, T., Alvarez, A.R., Rebolledo-Jaramillo, B., Klein, A.D., Winter, D., et al.. (2021). Proteomic analysis of niemann-pick type c hepatocytes reveals potential therapeutic targets for liver damage. Cells 10: 2159, https://doi.org/10.3390/cells10082159.Search in Google Scholar PubMed PubMed Central
Balderhaar, H.J.K. and Ungermann, C. (2013). CORVET and HOPS tethering complexes – coordinators of endosome and lysosome fusion. J. Cell Sci. 126: 1307–1316, https://doi.org/10.1242/jcs.107805.Search in Google Scholar PubMed
Barbosa, A.D., Sembongi, H., Su, W.M., Abreu, S., Reggiori, F., Carman, G.M., and Siniossoglou, S. (2015). Lipid partitioning at the nuclear envelope controls membrane biogenesis. Mol. Biol. Cell 26: 3641–3657, https://doi.org/10.1091/mbc.e15-03-0173.Search in Google Scholar
Bean, B.D.M., Dziurdzik, S.K., Kolehmainen, K.L., Fowler, C.M.S., Kwong, W.K., Grad, L.I., Davey, M., Schluter, C., and Conibear, E. (2018). Competitive organelle-specific adaptors recruit Vps13 to membrane contact sites. J. Cell Biol. 217: 3593–3607, https://doi.org/10.1083/jcb.201804111.Search in Google Scholar PubMed PubMed Central
Berger, A.C., Salazar, G., Styers, M.L., Newell-Litwa, K.A., Werner, E., Maue, R.A., Corbett, A.H., and Faundez, V. (2007). The subcellular localization of the Niemann-Pick Type C proteins depends on the adaptor complex AP-3. J. Cell Sci. 120: 3640–3652, https://doi.org/10.1242/jcs.03487.Search in Google Scholar PubMed
Bernardo, K., Hurwitz, R., Zenk, T., Desnick, R.J., Ferlinz, K., Schuchman, E.H., and Sandhoff, K. (1995). Purification, characterization, and biosynthesis of human acid ceramidase. J. Biol. Chem. 270: 11098–11102, https://doi.org/10.1074/jbc.270.19.11098.Search in Google Scholar PubMed
Bisinski, D.D., Castro, I.G., Mari, M., Walter, S., Fröhlich, F., Schuldiner, M., and González Montoro, A. (2022). Cvm1 is a component of multiple vacuolar contact sites required for sphingolipid homeostasis. J. Cell Biol. 221: e202103048, https://doi.org/10.1083/JCB.202103048/213309.Search in Google Scholar
Blanz, J., Groth, J., Zachos, C., Wehling, C., Saftig, P., and Schwake, M. (2010). Disease-causing mutations within the lysosomal integral membrane protein type 2 (LIMP-2) reveal the nature of binding to its ligand β-glucocerebrosidase. Hum. Mol. Genet. 19: 563–572, https://doi.org/10.1093/hmg/ddp523.Search in Google Scholar PubMed
Bohnert, M. (2020). Tether me, tether me not—dynamic organelle contact sites in metabolic rewiring. Dev. Cell 54: 212–225, https://doi.org/10.1016/j.devcel.2020.06.026.Search in Google Scholar PubMed
Brady, R.O., Kanfer, J.N., Bradley, R.M., and Shapiro, D. (1966). Demonstration of a deficiency of glucocerebroside-cleaving enzyme in Gaucher’s disease. J. Clin. Invest. 45: 1112–1115, https://doi.org/10.1172/jci105417.Search in Google Scholar
Brady, R.O., Kanfer, J., and Shapiro, D. (1965). The metabolism of glucocerebrosides: I. Purification and properties of a glucocerebroside-cleaving enzyme from spleen tissue. J. Biol. Chem. 240: 39–43, https://doi.org/10.1016/s0021-9258(18)97611-8.Search in Google Scholar
Braulke, T. and Bonifacino, J.S. (2009). Sorting of lysosomal proteins. Biochim. Biophys. Acta Mol. Cell Res. 1793: 605–614, https://doi.org/10.1016/j.bbamcr.2008.10.016.Search in Google Scholar PubMed
Brown, M.S. and Goldstein, J.L. (1986). A receptor-mediated pathway for cholesterol homeostasis. Science 232: 34–47, https://doi.org/10.1126/science.3513311.Search in Google Scholar PubMed
Cai, S., Wu, Y., Guillen-Samande, A., Hancock-Cerutt, W., Liu, J., and de Camilli, P. (2022). In situ architecture of the lipid transport protein VPS13C at ER-lysosome membrane contacts. Proc. Natl. Acad. Sci. U.S.A. 119: e2203769119, https://doi.org/10.1073/pnas.2203769119.Search in Google Scholar PubMed PubMed Central
Castellano, B.M., Thelen, A.M., Moldavski, O., Feltes, M., van der Welle, R.E.N., Mydock-McGrane, L., Jiang, X., van Eijkeren, R.J., Davis, O.B., Louie, S.M., et al.. (2017). Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex. Science 355: 1306–1311, https://doi.org/10.1126/science.aag1417.Search in Google Scholar PubMed PubMed Central
Chu, B.B., Liao, Y.C., Qi, W., Xie, C., Du, X., Wang, J., Yang, H., Miao, H.H., Li, B.L., and Song, B.L. (2015). Cholesterol transport through lysosome-peroxisome membrane contacts. Cell 161: 291–306, https://doi.org/10.1016/j.cell.2015.02.019.Search in Google Scholar PubMed
Chung, J., Torta, F., Masai, K., Lucast, L., Czapla, H., Tanner, L.B., Narayanaswamy, P., Wenk, M.R., Nakatsu, F., and de Camilli, P. (2015). PI4P/phosphatidylserine countertransport at ORP5- and ORP8-mediated ER - plasma membrane contacts. Science 349: 428–432, https://doi.org/10.1126/science.aab1370.Search in Google Scholar PubMed PubMed Central
Collins, M.P. and Forgac, M. (2020). Regulation and function of V-ATPases in physiology and disease. Biochim. Biophys. Acta Biomembr. 1862: 183341, https://doi.org/10.1016/j.bbamem.2020.183341.Search in Google Scholar PubMed PubMed Central
Cowles, C.R., Emr, S.D., and Horazdovsky, B.F. (1994). Mutations in the VPS45 gene, a SEC1 homologue, result in vacuolar protein sorting defects and accumulation of membrane vesicles. J. Cell Sci. 107: 3449–3459, https://doi.org/10.1242/jcs.107.12.3449.Search in Google Scholar PubMed
Cowles, C.R., Odorizzi, G., Payne, G.S., and Emr, S.D. (1997). The AP-3 adaptor complex is essential for cargo-selective transport to the yeast vacuole. Cell 91: 109–118, https://doi.org/10.1016/s0092-8674(01)80013-1.Search in Google Scholar PubMed
Dall, F., Stagi, M., Swan, L.E., and Laura Swan, C.E. (2022). In silico modeling human VPS13 proteins associated with donor and target membranes suggests lipid transfer mechanisms. Proteins: Struct. Funct. Bioinf., https://doi.org/10.1002/PROT.26446.Search in Google Scholar PubMed
Davis, O.B., Shin, H.R., Lim, C.Y., Wu, E.Y., Kukurugya, M., Maher, C.F., Perera, R.M., Ordonez, M.P., and Zoncu, R. (2021). NPC1-mTORC1 signaling couples cholesterol sensing to organelle homeostasis and is a targetable pathway in niemann-pick type C. Dev. Cell 56: 260–276.e7, https://doi.org/10.1016/j.devcel.2020.11.016.Search in Google Scholar PubMed PubMed Central
Day, K.J., Casler, J.C., and Glick, B.S. (2018). Budding yeast has a minimal endomembrane system. Dev. Cell 44: 56–72.e4, https://doi.org/10.1016/j.devcel.2017.12.014.Search in Google Scholar PubMed PubMed Central
Dong, R., Saheki, Y., Swarup, S., Lucast, L., Harper, J.W., and De Camilli, P. (2016). Endosome-ER contacts control actin nucleation and retromer function through VAP-dependent regulation of PI4P. Cell 166: 408–423, https://doi.org/10.1016/j.cell.2016.06.037.Search in Google Scholar PubMed PubMed Central
Düvel, K., Yecies, J.L., Menon, S., Raman, P., Lipovsky, A.I., Souza, A.L., Triantafellow, E., Ma, Q., Gorski, R., Cleaver, S., et al.. (2010). Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39: 171–183, https://doi.org/10.1016/j.molcel.2010.06.022.Search in Google Scholar PubMed PubMed Central
Du, X., Kumar, J., Ferguson, C., Schulz, T.A., Ong, Y.S., Hong, W., Prinz, W.A., Parton, R.G., Brown, A.J., and Yang, H. (2011). A role for oxysterol-binding protein–related protein 5 in endosomal cholesterol trafficking. J. Cell Biol. 192: 121–135, https://doi.org/10.1083/jcb.201004142.Search in Google Scholar PubMed PubMed Central
Eden, E.R., Sanchez-Heras, E., Tsapara, A., Sobota, A., Levine, T.P., and Futter, C.E. (2016). Annexin A1 tethers membrane contact sites that mediate ER to endosome cholesterol transport. Dev. Cell 37: 473–483, https://doi.org/10.1016/j.devcel.2016.05.005.Search in Google Scholar PubMed PubMed Central
Eisenberg-Bord, M., Shai, N., Schuldiner, M., and Bohnert, M. (2016). A tether is a tether is a tether: tethering at membrane contact sites. Dev. Cell 39: 395–409, https://doi.org/10.1016/j.devcel.2016.10.022.Search in Google Scholar PubMed
Eising, S., Esch, B., Wälte, M., Duarte, P.V., Walter, S., Ungermann, C., Bohnert, M., and Fröhlich, F. (2022). A lysosomal biogenesis map reveals the cargo spectrum of yeast vacuolar protein targeting pathways. J. Cell Biol. 221: e202107148, https://doi.org/10.1083/JCB.202107148/213011.Search in Google Scholar
Eising, S., Thiele, L., and Fröhlich, F. (2019). A systematic approach to identify recycling endocytic cargo depending on the garp complex. Elife 8: e42837, https://doi.org/10.7554/ELIFE.42837.Search in Google Scholar PubMed PubMed Central
Elbaz-Alon, Y., Eisenberg-Bord, M., Shinder, V., Stiller, S.B., Shimoni, E., Wiedemann, N., Geiger, T., and Schuldiner, M. (2015). Lam6 regulates the extent of contacts between organelles. Cell Rep. 12: 7–14, https://doi.org/10.1016/j.celrep.2015.06.022.Search in Google Scholar PubMed PubMed Central
Elbaz-Alon, Y., Rosenfeld-Gur, E., Shinder, V., Futerman, A.H., Geiger, T., and Schuldiner, M. (2014). A dynamic interface between vacuoles and mitochondria in yeast. Dev. Cell 30: 95–102, https://doi.org/10.1016/j.devcel.2014.06.007.Search in Google Scholar PubMed
Ferlinz, K., Hurwitz, R., and Sandhoff, K. (1991). Molecular basis of acid sphingomyelinase dificiency in a patient with Niemann-Pick disease type A. Biochem. Biophys. Res. Commun. 179: 1187–1191, https://doi.org/10.1016/0006-291x(91)91697-b.Search in Google Scholar PubMed
Ferlinz, K., Kopal, G., Bernardo, K., Linke, T., Bär, J., Breiden, B., Neumann, U., Lang, F., Schuchman, E.H., and Sandhoff, K. (2001). Human acid ceramidase: processing, glycosylation, and lysosomal targeting. J. Biol. Chem. 276: 35352–35360, https://doi.org/10.1074/jbc.m103066200.Search in Google Scholar
Fröhlich, F., Petit, C., Kory, N., Christiano, R., Hannibal-Bach, H.K., Graham, M., Liu, X., Ejsing, C.S., Farese, R.V., and Walther, T.C. (2015). The GARP complex is required for cellular sphingolipid homeostasis. Elife 4: e08712, https://doi.org/10.7554/ELIFE.08712.Search in Google Scholar PubMed PubMed Central
Ghosh, P., Dahms, N.M., and Kornfeld, S. (2003). Mannose 6-phosphate receptors: new twists in the tale. Nat. Rev. Mol. Cell Biol. 4: 202–213, https://doi.org/10.1038/nrm1050.Search in Google Scholar PubMed
González, A. and Hall, M.N. (2017). Nutrient sensing and TOR signaling in yeast and mammals. EMBO J. 36: 397–408, https://doi.org/10.15252/embj.201696010.Search in Google Scholar PubMed PubMed Central
González Montoro, A., Auffarth, K., Hönscher, C., Bohnert, M., Becker, T., Warscheid, B., Reggiori, F., van der Laan, M., Fröhlich, F., and Ungermann, C. (2018). Vps39 interacts with Tom40 to establish one of two functionally distinct vacuole-mitochondria contact sites. Dev. Cell 45: 621–636.e7, https://doi.org/10.1016/j.devcel.2018.05.011.Search in Google Scholar PubMed
González Montoro, A., Vargas Duarte, P., Auffarth, K., Walter, S., Fröhlich, F., and Ungermann, C. (2021). Subunit exchange among endolysosomal tethering complexes is linked to contact site formation at the vacuole. Mol. Biol. Cell 32: br14, https://doi.org/10.1091/mbc.E21-05-0227.Search in Google Scholar PubMed PubMed Central
Guillén-Samander, A., Leonzino, M., Hanna, M.G., Tang, N., Shen, H., and de Camilli, P. (2021). VPS13D bridges the ER to mitochondria and peroxisomes via Miro. J. Cell Biol. 220: e202010004, https://doi.org/10.1083/JCB.202010004.Search in Google Scholar PubMed PubMed Central
Gulshan, K. and Moye-Rowley, W.S. (2011). Vacuolar import of phosphatidylcholine requires the ATP-binding cassette transporter Ybt1. Traffic 12: 1257–1268, https://doi.org/10.1111/j.1600-0854.2011.01228.x.Search in Google Scholar PubMed PubMed Central
Hancock-Cerutti, W., Wu, Z., Xu, P., Yadavalli, N., Leonzino, M., Tharkeshwar, A.K., Ferguson, S.M., Shadel, G.S., and de Camilli, P. (2022). ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling. J. Cell Biol. 221, https://doi.org/10.1083/JCB.202106046.Search in Google Scholar PubMed PubMed Central
Hariri, H., Rogers, S., Ugrankar, R., Liu, Y.L., Feathers, J.R., and Henne, W.M. (2018). Lipid droplet biogenesis is spatially coordinated at ER–vacuole contacts under nutritional stress. EMBO Rep. 19: 57–72, https://doi.org/10.15252/embr.201744815.Search in Google Scholar PubMed PubMed Central
Hariri, H., Speer, N., Bowerman, J., Rogers, S., Fu, G., Reetz, E., Datta, S., Feathers, J.R., Ugrankar, R., Nicastro, D., et al.. (2019). Mdm1 maintains endoplasmic reticulum homeostasis by spatially regulating lipid droplet biogenesis. J. Cell Biol. 218: 1319–1334, https://doi.org/10.1083/jcb.201808119.Search in Google Scholar PubMed PubMed Central
Henne, W.M., Zhu, L., Balogi, Z., Stefan, C., Pleiss, J.A., and Emr, S.D. (2015). Mdm1/Snx13 is a novel ER–endolysosomal interorganelle tethering protein. J. Cell Biol. 210: 541–551, https://doi.org/10.1083/jcb.201503088.Search in Google Scholar PubMed PubMed Central
Heybrock, S., Kanerva, K., Meng, Y., Ing, C., Liang, A., Xiong, Z.J., Weng, X., Ah Kim, Y., Collins, R., Trimble, W., et al.. (2019). Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export. Nat. Commun. 10: 1–12, https://doi.org/10.1038/s41467-019-11425-0.Search in Google Scholar PubMed PubMed Central
Höglinger, D., Burgoyne, T., Sanchez-Heras, E., Hartwig, P., Colaco, A., Newton, J., Futter, C.E., Spiegel, S., Platt, F.M., and Eden, E.R. (2019). NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress. Nat. Commun. 10: 1–14, https://doi.org/10.1038/s41467-019-12152-2.Search in Google Scholar PubMed PubMed Central
Holthuis, J.C.M. and Menon, A.K. (2014). Lipid landscapes and pipelines in membrane homeostasis. Nature 510: 48–57, https://doi.org/10.1038/nature13474.Search in Google Scholar PubMed
Hönscher, C., Mari, M., Auffarth, K., Bohnert, M., Griffith, J., Geerts, W., van der Laan, M., Cabrera, M., Reggiori, F., and Ungermann, C. (2014). Cellular metabolism regulates contact sites between vacuoles and mitochondria. Dev. Cell 30: 86–94, https://doi.org/10.1016/j.devcel.2014.06.006.Search in Google Scholar PubMed
Hua, Z., Fatheddin, P., and Graham, T.R. (2002). An essential subfamily of Drs2p-related P-type ATPases is required for protein trafficking between Golgi complex and endosomal/vacuolar system. Mol. Biol. Cell 13: 3162–3177, https://doi.org/10.1091/mbc.e02-03-0172.Search in Google Scholar PubMed PubMed Central
Jeong, H., Park, J., Kim, H.I., Lee, M., Ko, Y.J., Lee, S., Jun, Y., and Lee, C. (2017). Mechanistic insight into the nucleus-vacuole junction based on the Vac8p-Nvj1p crystal structure. Proc. Natl. Acad. Sci. U.S.A. 114: E4539–E4548, https://doi.org/10.1073/pnas.1701030114.Search in Google Scholar PubMed PubMed Central
Klein, A., Henseler, M., Klein, C., Suzuki, K., Harzer, K., and Sandhoff, K. (1994). Sphingolipid activator protein D (sap-D) Stimulates the lysosomal degradation of ceramide in vivo. Biochem. Biophys. Res. Commun. 200: 1440–1448, https://doi.org/10.1006/bbrc.1994.1612.Search in Google Scholar PubMed
Koch, J., Gärtner, S., Li, C.M., Quintern, L.E., Bernardo, K., Levran, O., Schnabel, D., Desnick, R.J., Schuchman, E.H., and Sandhoff, K. (1996). Molecular cloning and characterization of a full-length complementary DNA encoding human acid ceramidase: identification of the first molecular lesion causing Farber disease. J. Biol. Chem. 271: 33110–33115, https://doi.org/10.1074/jbc.271.51.33110.Search in Google Scholar PubMed
Kumar, N., Leonzino, M., Hancock-Cerutti, W., Horenkamp, F.A., Li, P.Q., Lees, J.A., Wheeler, H., Reinisch, K.M., and de Camilli, P. (2018). VPS13A and VPS13C are lipid transport proteins differentially localized at ER contact sites. J. Cell Biol. 217: 3625–3639, https://doi.org/10.1083/jcb.201807019.Search in Google Scholar PubMed PubMed Central
Lang, A.B., Peter, A.T.A.T.J., Walter, P., and Kornmann, B. (2015). ER–mitochondrial junctions can be bypassed by dominant mutations in the endosomal protein Vps13. J. Cell Biol. 210: 883–890, https://doi.org/10.1083/jcb.201502105.Search in Google Scholar PubMed PubMed Central
Leonzino, M., Reinisch, K.M., and de Camilli, P. (2021). Insights into VPS13 properties and function reveal a new mechanism of eukaryotic lipid transport. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1866: 159003, https://doi.org/10.1016/j.bbalip.2021.159003.Search in Google Scholar PubMed PubMed Central
Lesage, S., Drouet, V., Majounie, E., Deramecourt, V., Jacoupy, M., Nicolas, A., Cormier-Dequaire, F., Hassoun, S.M., Pujol, C., Ciura, S., et al.. (2016). Loss of VPS13C function in autosomal-recessive parkinsonism causes mitochondrial dysfunction and increases PINK1/parkin-dependent mitophagy. Am. J. Hum. Genet. 98: 500–513, https://doi.org/10.1016/j.ajhg.2016.01.014.Search in Google Scholar PubMed PubMed Central
Levine, T.P. (2022). TMEM106B in humans and Vac7 and Tag1 in yeast are predicted to be lipid transfer proteins. Proteins: Struct. Funct. Bioinf. 90: 164–175, https://doi.org/10.1002/prot.26201.Search in Google Scholar PubMed
Levine, T.P. and Munro, S. (2001). Dual targeting of Osh1p, a yeast homologue of oxysterol-binding protein, to both the Golgi and the nucleus-vacuole junction. Mol. Biol. Cell 12: 1633–1644, https://doi.org/10.1091/mbc.12.6.1633.Search in Google Scholar PubMed PubMed Central
Lim, C.Y., Davis, O.B., Shin, H.R., Zhang, J., Berdan, C.A., Jiang, X., Counihan, J.L., Ory, D.S., Nomura, D.K., and Zoncu, R. (2019). ER–lysosome contacts enable cholesterol sensing by mTORC1 and drive aberrant growth signalling in Niemann–Pick type C. Nat. Cell Biol. 21: 1206–1218, https://doi.org/10.1038/s41556-019-0391-5.Search in Google Scholar PubMed PubMed Central
Liou, B., Haffey, W.D., Greis, K.D., and Grabowski, G.A. (2014). The LIMP-2/SCARB2 binding motif on acid β-glucosidase. J. Biol. Chem. 289: 30063–30074, https://doi.org/10.1074/jbc.m114.593616.Search in Google Scholar
Li, P.Q., Lees, J.A., Patrick Lusk, C., and Reinisch, K.M. (2020). Cryo-EM reconstruction of a VPS13 fragment reveals a long groove to channel lipids between membranes. J. Cell Biol. 219: e202001161, https://doi.org/10.1083/JCB.202001161.Search in Google Scholar
Liu, L.K., Choudhary, V., Toulmay, A., and Prinz, W.A. (2017). An inducible ER–Golgi tether facilitates ceramide transport to alleviate lipotoxicity. J. Cell Biol. 216: 131–147, https://doi.org/10.1083/jcb.201606059.Search in Google Scholar PubMed PubMed Central
Li, X., Saha, P., Lib, J., Blobel, G., and Pfeffer, S.R. (2016). Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle lumenal domain bound to NPC2. Proc. Natl. Acad. Sci. U.S.A. 113: 10079–10084, https://doi.org/10.1073/pnas.1611956113.Search in Google Scholar PubMed PubMed Central
Lloyd-Evans, E., Morgan, A.J., He, X., Smith, D.A., Elliot-Smith, E., Sillence, D.J., Churchill, G.C., Schuchman, E.H., Galione, A., and Platt, F.M. (2008). Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat. Med. 14: 1247–1255, https://doi.org/10.1038/nm.1876.Search in Google Scholar PubMed
Lu, A., Hsieh, F., Sharma, B.R., Vaughn, S.R., Enrich, C., and Pfeffer, S.R. (2022). CRISPR screens for lipid regulators reveal a role for ER-bound SNX13 in lysosomal cholesterol export. J. Cell Biol. 221: e202105060, https://doi.org/10.1083/JCB.202105060.Search in Google Scholar PubMed PubMed Central
Lürick, A., Gao, J., Kuhlee, A., Yavavli, E., Langemeyer, L., Perz, A., Raunser, S., and Ungermann, C. (2017). Multivalent Rab interactions determine tether-mediated membrane fusion. Mol. Biol. Cell 28: 322–332, https://doi.org/10.1091/mbc.e16-11-0764.Search in Google Scholar
Marcusson, E.G., Horazdovsky, B.F., Cereghino, J.L., Gharakhanian, E., and Emr, S.D. (1994). The sorting receptor for yeast vacuolar carboxypeptidase Y is encoded by the VPS10 gene. Cell 77: 579–586, https://doi.org/10.1016/0092-8674(94)90219-4.Search in Google Scholar PubMed
Marshansky, V., Rubinstein, J.L., and Grüber, G. (2014). Eukaryotic V-ATPase: novel structural findings and functional insights. Biochim. Biophys. Acta, Bioenerg. 1837: 857–879, https://doi.org/10.1016/j.bbabio.2014.01.018.Search in Google Scholar PubMed
Mesmin, B., Bigay, J., Von Filseck, J.M., Lacas-Gervais, S., Drin, G., and Antonny, B. (2013). A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER-Golgi tether OSBP. Cell 155: 830–843, https://doi.org/10.1016/j.cell.2013.09.056.Search in Google Scholar PubMed
Mesmin, B., Bigay, J., Polidori, J., Jamecna, D., Lacas-Gervais, S., and Antonny, B. (2017). Sterol transfer, PI4P consumption, and control of membrane lipid order by endogenous OSBP. EMBO J. 36: 3156–3174, https://doi.org/10.15252/embj.201796687.Search in Google Scholar PubMed PubMed Central
Moeller, C.H. and Thomson, W.W. (1979). Uptake of lipid bodies by the yeast vacuole involving areas of the tonoplast depleted of intramembranous particles. J. Ultrastruct. Res. 68: 38–45, https://doi.org/10.1016/s0022-5320(79)90140-0.Search in Google Scholar PubMed
Mosen, P., Sanner, A., Singh, J., and Winter, D. (2021). Targeted quantification of the lysosomal proteome in complex samples. Proteomes 9: 4, https://doi.org/10.3390/proteomes9010004.Search in Google Scholar PubMed PubMed Central
Murley, A., Sarsam, R.D., Toulmay, A., Yamada, J., Prinz, W.A., and Nunnari, J. (2015). Ltc1 is an ER-localized sterol transporter and a component of ER–mitochondria and ER–vacuole contacts. J. Cell Biol. 209: 539–548, https://doi.org/10.1083/jcb.201502033.Search in Google Scholar PubMed PubMed Central
Murley, A., Yamada, J., Niles, B.J., Toulmay, A., Prinz, W.A., Powers, T., and Nunnari, J. (2017). Sterol transporters at membrane contact sites regulate TORC1 and TORC2 signaling. J. Cell Biol. 216: 2679–2689, https://doi.org/10.1083/jcb.201610032.Search in Google Scholar PubMed PubMed Central
Neculai, D., Schwake, M., Ravichandran, M., Zunke, F., Collins, R.F., Peters, J., Neculai, M., Plumb, J., Loppnau, P., Pizarro, J.C., et al.. (2013). Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36. Nature 504: 172–176, https://doi.org/10.1038/nature12684.Search in Google Scholar PubMed
Nishimura, A.L., Mitne-Neto, M., Silva, H.C.A., Richieri-Costa, A., Middleton, S., Cascio, D., Kok, F., Oliveira, J.R.M., Gillingwater, T., Webb, J., et al.. (2004). A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am. J. Hum. Genet. 75: 822–831, https://doi.org/10.1086/425287.Search in Google Scholar PubMed PubMed Central
Ni, X. and Morales, C.R. (2006). The lysosomal trafficking of acid sphingomyelinase is mediated by sortilin and mannose 6-phosphate receptor. Traffic 7: 889–902, https://doi.org/10.1111/j.1600-0854.2006.00429.x.Search in Google Scholar PubMed
Owen, J.L., Zhang, Y., Bae, S.H., Farooqi, M.S., Liang, G., Hammer, R.E., Goldstein, J.L., and Brown, M.S. (2012). Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. Proc. Natl. Acad. Sci. U.S.A. 109: 16184–16189, https://doi.org/10.1073/pnas.1213343109.Search in Google Scholar PubMed PubMed Central
Pan, X., Roberts, P., Chen, Y., Kvam, E., Shulga, N., Huang, K., Lemmon, S., and Goldfarb, D.S. (2000). Nucleus-vacuole junctions in Saccharomyces cerevisiae are formed through the direct interaction of Vac8p with Nvj1p. Mol. Biol. Cell 11: 2445–2457, https://doi.org/10.1091/mbc.11.7.2445.Search in Google Scholar PubMed PubMed Central
Pechincha, C., Groessl, S., Kalis, R., de Almeida, M., Zanotti, A., Wittmann, M., Schneider, M., de Campos, R.P., Rieser, S., Brandstetter, M., et al.. (2022). Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins. Science 378: eabn5637, https://doi.org/10.1126/science.abn5637.Search in Google Scholar PubMed
Peter, A.T.J., Herrmann, B., Antunes, D., Rapaport, D., Dimmer, K.S., and Kornmann, B. (2017). Vps13-Mcp1 interact at vacuole–mitochondria interfaces and bypass ER–mitochondria contact sites. J. Cell Biol. 216: 3219–3229, https://doi.org/10.1083/jcb.201610055.Search in Google Scholar PubMed PubMed Central
Petit, C.S., Lee, J.J., Boland, S., Swarup, S., Christiano, R., Lai, Z.W., Mejhert, N., Elliott, S.D., McFall, D., Haque, S., et al.. (2020). Inhibition of sphingolipid synthesis improves outcomes and survival in GARP mutant wobbler mice, a model of motor neuron degeneration. Proc. Natl. Acad. Sci. U.S.A. 117: 10565–10574, https://doi.org/10.1073/pnas.1913956117.Search in Google Scholar PubMed PubMed Central
Ponsford, A.H., Ryan, T.A., Raimondi, A., Cocucci, E., Wycislo, S.A., Fröhlich, F., Swan, L.E., and Stagi, M. (2021). Live imaging of intra-lysosome pH in cell lines and primary neuronal culture using a novel genetically encoded biosensor. Autophagy 17: 1500–1518, https://doi.org/10.1080/15548627.2020.1771858.Search in Google Scholar PubMed PubMed Central
Prinz, W.A., Toulmay, A., and Balla, T. (2019). The functional universe of membrane contact sites. Nat. Rev. Mol. Cell Biol. 21: 7–24, https://doi.org/10.1038/s41580-019-0180-9.Search in Google Scholar PubMed
Qian, H., Wu, X., Du, X., Yao, X., Zhao, X., Lee, J., Yang, H., and Yan, N. (2020). Structural basis of low-pH-dependent lysosomal cholesterol egress by NPC1 and NPC2. Cell 182: 98–111.e18, https://doi.org/10.1016/j.cell.2020.05.020.Search in Google Scholar PubMed
Raiborg, C., Wenzel, E.M., and Stenmark, H. (2015). ER–endosome contact sites: molecular compositions and functions. EMBO J. 34: 1848–1858, https://doi.org/10.15252/embj.201591481.Search in Google Scholar PubMed PubMed Central
Rayermann, S.P., Rayermann, G.E., Cornell, C.E., Merz, A.J., and Keller, S.L. (2017). Hallmarks of reversible separation of living, unperturbed cell membranes into two liquid phases. Biophys. J. 113: 2425–2432, https://doi.org/10.1016/j.bpj.2017.09.029.Search in Google Scholar PubMed PubMed Central
Reczek, D., Schwake, M., Schröder, J., Hughes, H., Blanz, J., Jin, X., Brondyk, W., van Patten, S., Edmunds, T., and Saftig, P. (2007). LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of β-glucocerebrosidase. Cell 131: 770–783, https://doi.org/10.1016/j.cell.2007.10.018.Search in Google Scholar PubMed
Reinisch, K.M. and Prinz, W.A. (2021). Mechanisms of nonvesicular lipid transport. J. Cell Biol. 220: e202012058, https://doi.org/10.1083/JCB.202012058/211813.Search in Google Scholar
Richards, C.M., Jabs, S., Qiao, W., Varanese, L.D., Schweizer, M., Mosen, P.R., Riley, N.M., Klüssendorf, M., Zengel, J.R., Flynn, R.A., et al.. (2022). The human disease gene LYSET is essential for lysosomal enzyme transport and viral infection. Science 378: eabn5648, https://doi.org/10.1126/science.abn5648.Search in Google Scholar PubMed PubMed Central
Roberts, P., Moshitch-Moshkovitz, S., Kvam, E., O’Toole, E., Winey, M., and Goldfarb, D.S. (2003). Piecemeal microautophagy of nucleus in Saccharomyces cerevisiae. Mol. Biol. Cell 14: 129–141, https://doi.org/10.1091/mbc.e02-08-0483.Search in Google Scholar PubMed PubMed Central
Rocha, N., Kuijl, C., van der Kant, R., Janssen, L., Houben, D., Janssen, H., Zwart, W., and Neefjes, J. (2009). Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7-RILP-p150Glued and late endosome positioning. J. Cell Biol. 185: 1209–1225, https://doi.org/10.1083/jcb.200811005.Search in Google Scholar PubMed PubMed Central
Rogers, S., Hariri, H., Wood, N.E., Speer, N.O., and Henne, W.M. (2021). Glucose restriction drives spatial reorganization of mevalonate metabolism. Elife 10: e62591, https://doi.org/10.7554/ELIFE.62591.Search in Google Scholar PubMed PubMed Central
Rothman, J.H. and Stevens, T.H. (1986). Protein sorting in yeast: mutants defective in vacuole biogenesis mislocalize vacuolar proteins into the late secretory pathway. Cell 47: 1041–1051, https://doi.org/10.1016/0092-8674(86)90819-6.Search in Google Scholar PubMed
Rowland, A.A., Chitwood, P.J., Phillips, M.J., and Voeltz, G.K. (2014). ER contact sites define the position and timing of endosome fission. Cell 159: 1027–1041, https://doi.org/10.1016/j.cell.2014.10.023.Search in Google Scholar PubMed PubMed Central
Schulze, R.J., Krueger, E.W., Weller, S.G., Johnson, K.M., Casey, C.A., Schott, M.B., and McNiven, M.A. (2020). Direct lysosome-based autophagy of lipid droplets in hepatocytes. Proc. Natl. Acad. Sci. U.S.A. 117: 32443–32452, https://doi.org/10.1073/pnas.2011442117.Search in Google Scholar PubMed PubMed Central
Schwake, M., Schröder, B., and Saftig, P. (2013). Lysosomal membrane proteins and their central role in physiology. Traffic 14: 739–748, https://doi.org/10.1111/tra.12056.Search in Google Scholar PubMed
Scorrano, L., de Matteis, M.A., Emr, S., Giordano, F., Hajnóczky, G., Kornmann, B., Lackner, L.L., Levine, T.P., Pellegrini, L., Reinisch, K., et al.. (2019). Coming together to define membrane contact sites. Nat. Commun. 10: 1–11, https://doi.org/10.1038/s41467-019-09253-3.Search in Google Scholar PubMed PubMed Central
Seo, A.Y., Lau, P.W., Feliciano, D., Sengupta, P., le Gros, M.A., Cinquin, B., Larabell, C.A., and Lippincott-Schwartz, J. (2017). AMPK and vacuole-associated Atg14p orchestrate μ-lipophagy for energy production and long-term survival under glucose starvation. Elife 6: e21690, https://doi.org/10.7554/ELIFE.21690.Search in Google Scholar PubMed PubMed Central
Shin, H.R., Citron, Y.R., Wang, L., Tribouillard, L., Goul, C.S., Stipp, R., Sugasawa, Y., Jain, A., Samson, N., Lim, C.Y., et al.. (2022). Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1. Science 377: 1290–1298, https://doi.org/10.1126/science.abg6621.Search in Google Scholar PubMed PubMed Central
Shvarev, D., Schoppe, J., König, C., Perz, A., Füllbrunn, N., Kiontke, S., Langemeyer, L., Januliene, D., Schnelle, K., Kümmel, D., et al.. (2022). Structure of the HOPS tethering complex, a lysosomal membrane fusion machinery. Elife 11: e80901, https://doi.org/10.7554/ELIFE.80901.Search in Google Scholar PubMed PubMed Central
Takagi, K., Iwamoto, K., Kobayashi, S., Horiuchi, H., Fukuda, R., and Ohta, A. (2012). Involvement of Golgi-associated retrograde protein complex in the recycling of the putative Dnf aminophospholipid flippases in yeast. Biochem. Biophys. Res. Commun. 417: 490–494, https://doi.org/10.1016/j.bbrc.2011.11.147.Search in Google Scholar PubMed
Tosal-Castano, S., Peselj, C., Kohler, V., Habernig, L., Berglund, L.L., Ebrahimi, M., Vögtle, F.N., Höög, J., Andréasson, C., and Büttner, S. (2021). Snd3 controls nucleus-vacuole junctions in response to glucose signaling. Cell Rep. 34: 108637, https://doi.org/10.1016/j.celrep.2020.108637.Search in Google Scholar PubMed
Toulmay, A. and Prinz, W.A. (2013). Direct imaging reveals stable, micrometer-scale lipid domains that segregate proteins in live cells. J. Cell Biol. 202: 35–44, https://doi.org/10.1083/jcb.201301039.Search in Google Scholar PubMed PubMed Central
von Filseck, J.M., Čopič, A., Delfosse, V., Vanni, S., Jackson, C.L., Bourguet, W., and Drin, G. (2015a). Phosphatidylserine transport by ORP/Osh proteins is driven by phosphatidylinositol 4-phosphate. Science 349: 432–436, https://doi.org/10.1126/science.aab1346.Search in Google Scholar PubMed
von Filseck, J.M., Vanni, S., Mesmin, B., Antonny, B., and Drin, G. (2015b). A phosphatidylinositol-4-phosphate powered exchange mechanism to create a lipid gradient between membranes. Nat. Commun. 6: 1–12, https://doi.org/10.1038/ncomms7671.Search in Google Scholar PubMed
Wang, C.W., Miao, Y.H., and Chang, Y.S. (2014). A sterol-enriched vacuolar microdomain mediates stationary phase lipophagy in budding yeast. J. Cell Biol. 206: 357–366, https://doi.org/10.1083/jcb.201404115.Search in Google Scholar PubMed PubMed Central
Wilhelm, L.P., Wendling, C., Védie, B., Kobayashi, T., Chenard, M.P., Tomasetto, C., Drin, G., and Alpy, F. (2017). STARD3 mediates endoplasmic reticulum-to-endosome cholesterol transport at membrane contact sites. EMBO J. 36: 1412–1433, https://doi.org/10.15252/embj.201695917.Search in Google Scholar PubMed PubMed Central
Willnow, T.E., Petersen, C.M., and Nykjaer, A. (2008). VPS10P-domain receptors — regulators of neuronal viability and function. Nat. Rev. Neurosci. 9: 899–909, https://doi.org/10.1038/nrn2516.Search in Google Scholar PubMed
Winkler, M.B.L., Kidmose, R.T., Szomek, M., Thaysen, K., Rawson, S., Muench, S.P., Wüstner, D., and Pedersen, B.P. (2019). Structural insight into eukaryotic sterol transport through Niemann-Pick Type C proteins. Cell 179: 485–497.e18, https://doi.org/10.1016/j.cell.2019.08.038.Search in Google Scholar PubMed
Wong, L.H., Gatta, A.T., and Levine, T.P. (2018). Lipid transfer proteins: the lipid commute via shuttles, bridges and tubes. Nat. Rev. Mol. Cell Biol. 20: 85–101, https://doi.org/10.1038/s41580-018-0071-5.Search in Google Scholar PubMed
Xu, J., Dang, Y., Ren, Y.R., and Liu, J.O. (2010). Cholesterol trafficking is required for mTOR activation in endothelial cells. Proc. Natl. Acad. Sci. U.S.A. 107: 4764–4769, https://doi.org/10.1073/pnas.0910872107.Search in Google Scholar PubMed PubMed Central
Xu, S., Benoff, B., Liou, H.L., Lobel, P., and Stock, A.M. (2007). Structural basis of sterol binding by NPC2, a lysosomal protein deficient in niemann-pick type C2 disease. J. Biol. Chem. 282: 23525–23531, https://doi.org/10.1074/jbc.m703848200.Search in Google Scholar PubMed PubMed Central
Yecies, J.L., Zhang, H.H., Menon, S., Liu, S., Yecies, D., Lipovsky, A.I., Gorgun, C., Kwiatkowski, D.J., Hotamisligil, G.S., Lee, C.H., et al.. (2011). Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metabol. 14: 21–32, https://doi.org/10.1016/j.cmet.2011.07.004.Search in Google Scholar
Zeng, J., Racicott, J., and Morales, C.R. (2009). The inactivation of the sortilin gene leads to a partial disruption of prosaposin trafficking to the lysosomes. Exp. Cell Res. 315: 3112–3124, https://doi.org/10.1016/j.yexcr.2009.08.016.Search in Google Scholar PubMed
Zhang, S., Ren, J., Li, H., Zhang, Q., Armstrong, J.S., Munn, A.L., and Yang, H. (2004). Ncr1p, the yeast ortholog of mammalian Niemann-Pick C1 protein, is dispensable for endocytic transport. Traffic 5: 1017–1030, https://doi.org/10.1111/j.1600-0854.2004.00241.x.Search in Google Scholar PubMed
Zhao, Y., Ren, J., Padilla-Parra, S., Fry, E.E., and Stuart, D.I. (2014). Lysosome sorting of β-glucocerebrosidase by LIMP-2 is targeted by the mannose 6-phosphate receptor. Nat. Commun. 5: 1–12, https://doi.org/10.1038/ncomms5321.Search in Google Scholar PubMed PubMed Central
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