Published by De Gruyter

Volume 399 Issue 10 - Highlight: Sphingolipids in Infectious Biology and Immunology

Issue of Biological Chemistry

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Contents
Journal Overview

Publicly Available September 12, 2018

Frontmatter

Page range: i-iv

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August 31, 2018

Highlight: sphingolipids in infectious biology and immunology

Alexander Carpinteiro, Katrin Anne Becker, Erich Gulbins

Page range: 1113-1113

September 7, 2018

Sphingolipids in early viral replication and innate immune activation

Judith Bezgovsek, Erich Gulbins, Sarah-Kim Friedrich, Karl S. Lang, Vikas Duhan

Page range: 1115-1123

Abstract

In this review, we summarize the mechanisms by which sphingolipids modulate virus multiplication and the host innate immune response, using a number of host-virus systems as illustrative models. Sphingolipids exert diverse functions, both at the level of the viral life cycle and in the regulation of antiviral immune responses. Sphingolipids may influence viral replication in three ways: by serving as (co)receptors during viral entry, by modulating virus replication, and by shaping the antiviral immune response. Several studies have demonstrated that sphingosine kinases (SphK) and their product, sphingosine-1-phosphate (S1P), enhance the replication of influenza, measles, and hepatitis B virus (HBV). In contrast, ceramides, particularly S1P and SphK1, influence the expression of type I interferon (IFN-I) by modulating upstream antiviral signaling and enhancing dendritic cell maturation, differentiation, and positioning in tissue. The synthetic molecule α-galactosylceramide has also been shown to stimulate natural killer cell activation and interferon (IFN)-γ secretion. However, to date, clinical trials have failed to demonstrate any clinical benefit for sphingolipids in the treatment of cancer or HBV infection. Taken together, these findings show that sphingolipids play an important and underappreciated role in the control of virus replication and the innate immune response.

June 30, 2018

The function of sphingomyelinases in mycobacterial infections

Yuqing Wu, Erich Gulbins, Heike Grassmé

Page range: 1125-1133

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis , is one of the deadliest and most important infectious diseases worldwide. The sphingomyelinase/ceramide system, which has been shown several times to be a crucial factor in the internalization, processing and killing of diverse pathogens, also modulates the pro-inflammatory response and the state of mycobacteria in macrophages. Both acid and neutral sphingomyelinases are important in this activity. However, studies of the role of sphingomyelinases in TB are still at an early stage.

July 20, 2018

The role of acid sphingomyelinase and modulation of sphingolipid metabolism in bacterial infection

Alexander Simonis, Alexandra Schubert-Unkmeir

Page range: 1135-1146

Abstract

Acid sphingomyelinase (ASM) is a key enzyme in sphingolipid metabolism that converts sphingomyelin to ceramide, thereby modulating membrane structures and signal transduction. Bacterial pathogens can manipulate ASM activity and function, and use host sphingolipids during multiple steps of their infection process. An increase in ceramides upon infection results in the formation of ceramide-enriched membrane platforms that serve to cluster receptor molecules and organize intracellular signaling molecules, thus facilitating bacterial uptake. In this review, we focus on how extracellular bacterial pathogens target ASM and modulate membrane properties and signaling pathways to gain entry into eukaryotic cells or induce cell death. We describe how intracellular pathogens interfere with the intralysosomal functions of ASM to favor replication and survival. In addition, bacteria utilize their own sphingomyelinases as virulence factors to modulate sphingolipid metabolism. The potential of ASM as a target for treating bacterial infections is also discussed.

February 2, 2018

The neutral sphingomyelinase 2 in T cell receptor signaling and polarity

Lena Collenburg, Sibylle Schneider-Schaulies, Elita Avota

Page range: 1147-1155

Abstract

By hydrolyzing its substrate sphingomyelin at the cytosolic leaflet of cellular membranes, the neutral sphingomyelinase 2 (NSM2) generates microdomains which serve as docking sites for signaling proteins and thereby, functions to regulate signal relay. This has been particularly studied in cellular stress responses while the regulatory role of this enzyme in the immune cell compartment has only recently emerged. In T cells, phenotypic polarization by co-ordinated cytoskeletal remodeling is central to motility and interaction with endothelial or antigen-presenting cells during tissue recruitment or immune synapse formation, respectively. This review highlights studies adressing the role of NSM2 in T cell polarity in which the enzyme plays a major role in regulating cytoskeletal dynamics.

June 19, 2018

Click reactions with functional sphingolipids

Julian Fink, Jürgen Seibel

Page range: 1157-1168

Abstract

Sphingolipids and glycosphingolipids can regulate cell recognition and signalling. Ceramide and sphingosine-1-phosphate are major players in the sphingolipid pathways and are involved in the initiation and regulation of signalling, apoptosis, stress responses and infection. Specific chemically synthesised sphingolipid derivatives containing small functionalities like azide or alkyne can mimic the biological properties of natural lipid species, which turns them into useful tools for the investigation of the highly complex sphingolipid metabolism by rapid and selective ‘click chemistry’ using sensitive tags like fluorophores. Subsequent analysis by various fluorescence microscopy techniques or mass spectrometry allows the identification and quantification of the corresponding sphingolipid metabolites as well as the research of associated enzymes. Here we present an overview of recent advances in the synthesis of ceramide and sphingosine analogues for bioorthogonal click reactions to study biosynthetic pathways and localization of sphingolipids for the development of novel therapeutics against lipid-dependent diseases.

June 19, 2018

Sphingolipids in inflammatory hypoxia

Ulrike G. Glaser, Joachim Fandrey

Page range: 1169-1174

Abstract

Hypoxia due to rapid tumor growth with impaired neovascularization and inflammation resulting from immune cell activation are hallmarks of cancer. Hypoxia-inducible factors control transcriptional adaptation in response to low oxygen conditions, both in tumor and immune cells. In addition, sphingolipids become increasingly recognized as important cell mediators in tumor and inflammatory hypoxia. Recent studies have identified acid sphingomyelinase (ASM), a central enzyme in the sphingolipid metabolism, as a regulator of several types of stress stimuli pathways and an important player in the tumor microenvironment. Therefore, this review will address the connection between the hypoxic response and the ASM/ceramide system in the context of inflammatory hypoxia.

June 19, 2018

CD4⁺ Foxp3⁺ regulatory T cell-mediated immunomodulation by anti-depressants inhibiting acid sphingomyelinase

Jürgen Schneider-Schaulies, Niklas Beyersdorf

Page range: 1175-1182

Abstract

Acid sphingomyelinase (ASM) is the rate-limiting enzyme cleaving sphingomyelin into ceramide and phosphorylcholin. CD4 + Foxp3 + regulatory T (Treg) cells depend on CD28 signaling for their survival and function, a receptor that activates the ASM. Both, basal and CD28-induced ASM activities are higher in Treg cells than in conventional CD4 + T (Tconv) cells. In ASM-deficient ( Smpd1 −/− ) as compared to wt mice, membranes of T cells contain 7–10-fold more sphingomyelin and two- to three-fold more ceramide, and are in a state of higher order than membranes of T cells from wt mice, which may facilitate their activation. Indeed, the frequency of Treg cells among CD4 + T cells in ASM-deficient mice and their suppressive activity in vitro are increased. Moreover, in vitro stimulation of ASM-deficient T cells in the presence of TGF-β and IL-2 leads to higher numbers of induced Treg cells. Pharmacological inhibition of the ASM with a clinically used tricyclic antidepressant such as amitriptyline in mice or in tissue culture of murine or human T cells induces higher frequencies of Treg cells among CD4 + T cells within a few days. This fast alteration of the balance between T cell populations in vitro is due to the elevated cell death of Tconv cells and protection of the CD25 high Treg cells by IL-2. Together, these findings suggest that ASM-inhibiting antidepressants, including a fraction of the serotonin re-uptake inhibitors (SSRIs), are moderately immunosuppressive and should be considered for the therapy of inflammatory and autoimmune disorders.

June 21, 2018

Pathological manifestations of Farber disease in a new mouse model

Nadine Beckmann, Stephanie Kadow, Fabian Schumacher, Joachim R. Göthert, Stefanie Kesper, Annette Draeger, Walter J. Schulz-Schaeffer, Jiang Wang, Jan U. Becker, Melanie Kramer, Claudine Kühn, Burkhard Kleuser, Katrin Anne Becker, Erich Gulbins, Alexander Carpinteiro

Page range: 1183-1202

Abstract

Farber disease (FD) is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments are clinically available and affected patients have a severely shortened lifespan. Due to the low incidence, the pathogenesis of FD is still poorly understood. Here, we report a novel acid ceramidase mutant mouse model that enables the study of pathogenic mechanisms of FD and ceramide accumulation. Asah1 tmEx1 mice were generated by deletion of the acid ceramidase signal peptide sequence. The effects on lysosomal targeting and activity of the enzyme were assessed. Ceramide and sphingomyelin levels were quantified by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and disease manifestations in several organ systems were analyzed by histology and biochemistry. We show that deletion of the signal peptide sequence disrupts lysosomal targeting and enzyme activity, resulting in ceramide and sphingomyelin accumulation. The affected mice fail to thrive and die early. Histiocytic infiltrations were observed in many tissues, as well as lung inflammation, liver fibrosis, muscular disease manifestations and mild kidney injury. Our new mouse model mirrors human FD and thus offers further insights into the pathogenesis of this disease. In the future, it may also facilitate the development of urgently needed therapies.

May 1, 2018

Pulmonary infection of cystic fibrosis mice with Staphylococcus aureus requires expression of α-toxin

Simone Keitsch, Joachim Riethmüller, Matthias Soddemann, Carolin Sehl, Barbara Wilker, Michael J. Edwards, Charles C. Caldwell, Martin Fraunholz, Erich Gulbins, Katrin Anne Becker

Page range: 1203-1213

Abstract

Pulmonary infections of cystic fibrosis (CF) patients with Staphylococcus aureus ( S. aureus ) occur very early in the disease. The molecular details that cause infection-susceptibility of CF patients to and mediate infection with S. aureus are poorly characterized. Therefore, we aimed to identify the role of α-toxin, a major S. aureus toxin, for pulmonary infection of CF mice. Infection with S. aureus JE2 resulted in severe pneumonia in CF mice, while wildtype mice were almost unaffected. Deficiency of α-toxin in JE2-Δhla reduced the pathogenicity of S. aureus in CF mice. However, CF mice were still more susceptible to the mutant S. aureus strain than wildtype mice. The S. aureus JE2 induced a marked increase of ceramide and a downregulation of sphingosine and acid ceramidase expression in bronchi of CF mice. Deletion of α-toxin reduced these changes after infection of CF mice. Similar changes were observed in wildtype mice, but at much lower levels. Our data indicate that expression of α-toxin is a major factor causing S. aureus infections in CF mice. Wildtype S. aureus induces a marked increase of ceramide and a reduction of sphingosine and acid ceramidase expression in bronchial epithelial cells of wildtype and CF mice, changes that determine infection susceptibility.

Minireview

September 7, 2018

Roles of the nucleotide exchange factor and chaperone Hsp110 in cellular proteostasis and diseases of protein misfolding

Unekwu M. Yakubu, Kevin A. Morano

Page range: 1215-1221

Abstract

Cellular protein homeostasis (proteostasis) is maintained by a broad network of proteins involved in synthesis, folding, triage, repair and degradation. Chief among these are molecular chaperones and their cofactors that act as powerful protein remodelers. The growing realization that many human pathologies are fundamentally diseases of protein misfolding (proteopathies) has generated interest in understanding how the proteostasis network impacts onset and progression of these diseases. In this minireview, we highlight recent progress in understanding the enigmatic Hsp110 class of heat shock protein that acts as both a potent nucleotide exchange factor to regulate activity of the foldase Hsp70, and as a passive chaperone capable of recognizing and binding cellular substrates on its own, and its integration into the proteostasis network.

Research Articles/Short Communications

Proteolysis

Open Access June 27, 2018

The two cathepsin B-like proteases of Arabidopsis thaliana are closely related enzymes with discrete endopeptidase and carboxydipeptidase activities

Andreas Porodko, Ana Cirnski, Drazen Petrov, Teresa Raab, Melanie Paireder, Bettina Mayer, Daniel Maresch, Lisa Nika, Martin L. Biniossek, Patrick Gallois, Oliver Schilling, Chris Oostenbrink, Marko Novinec, Lukas Mach

Page range: 1223-1235

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Abstract

The genome of the model plant Arabidopsis thaliana encodes three paralogues of the papain-like cysteine proteinase cathepsin B (AtCathB1, AtCathB2 and AtCathB3), whose individual functions are still largely unknown. Here we show that a mutated splice site causes severe truncations of the AtCathB1 polypeptide, rendering it catalytically incompetent. By contrast, AtCathB2 and AtCathB3 are effective proteases which display comparable hydrolytic properties and share most of their substrate specificities. Site-directed mutagenesis experiments demonstrated that a single amino acid substitution (Gly 336 →Glu) is sufficient to confer AtCathB2 with the capacity to tolerate arginine in its specificity-determining S2 subsite, which is otherwise a hallmark of AtCathB3-mediated cleavages. A degradomics approach utilizing proteome-derived peptide libraries revealed that both enzymes are capable of acting as endopeptidases and exopeptidases, releasing dipeptides from the C-termini of substrates. Mutation of the carboxydipeptidase determinant His 207 also affected the activity of AtCathB2 towards non-exopeptidase substrates, highlighting mechanistic differences between plant and human cathepsin B. This was also noted in molecular modeling studies which indicate that the occluding loop defining the dual enzymatic character of cathepsin B does not obstruct the active-site cleft of AtCathB2 to the same extent as in its mammalian orthologues.

About this journal

Objective
Biological Chemistry keeps you up-to-date with all new developments in the molecular life sciences. In addition to original research reports, authoritative reviews written by leading researchers in the field keep you informed about the latest advances in the molecular life sciences. Rapid, yet rigorous reviewing ensures fast access to recent research results of exceptional significance in the biological sciences.

Topics

general biochemistry
pathobiochemistry
structural biology
molecular and cellular biology
genetics and epigenetics
molecular medicine
cancer research
virology
immunology
plant molecular biology and biochemistry
novel experimental methodologies

Article formats
Research Articles, Short Communications, Reviews and Minireviews
Reviews are published by invitation only, but suggestions to the Editor-in-Chief are welcome.

The journal is associated with the German Society for Biochemistry and Molecular Biology (GBM).

Volume 399 Issue 10 - Highlight: Sphingolipids in Infectious Biology and Immunology

Issue of Biological Chemistry

Frontmatter

Highlight: sphingolipids in infectious biology and immunology

Sphingolipids in early viral replication and innate immune activation

Abstract

The function of sphingomyelinases in mycobacterial infections

Abstract

The role of acid sphingomyelinase and modulation of sphingolipid metabolism in bacterial infection

Abstract

The neutral sphingomyelinase 2 in T cell receptor signaling and polarity

Abstract

Click reactions with functional sphingolipids

Abstract

Sphingolipids in inflammatory hypoxia

Abstract

CD4+ Foxp3+ regulatory T cell-mediated immunomodulation by anti-depressants inhibiting acid sphingomyelinase

Abstract

Pathological manifestations of Farber disease in a new mouse model

Abstract

Pulmonary infection of cystic fibrosis mice with Staphylococcus aureus requires expression of α-toxin

Abstract

Roles of the nucleotide exchange factor and chaperone Hsp110 in cellular proteostasis and diseases of protein misfolding

Abstract

The two cathepsin B-like proteases of Arabidopsis thaliana are closely related enzymes with discrete endopeptidase and carboxydipeptidase activities

Abstract

CD4⁺ Foxp3⁺ regulatory T cell-mediated immunomodulation by anti-depressants inhibiting acid sphingomyelinase