Protein S-palmitoylation in immunity

S-palmitoylation is a reversible posttranslational lipid modification of proteins. It controls protein activity, stability, trafficking and protein–protein interactions. Recent global profiling of immune cells and targeted analysis have identified many S-palmitoylated immunity-associated proteins. Here, we review S-palmitoylated immune receptors and effectors, and their dynamic regulation at cellular membranes to generate specific and balanced immune responses. We also highlight how this understanding can drive therapeutic advances to pharmacologically modulate immune responses.

[1]  B. Raught,et al.  FASN inhibitor TVB-3166 prevents S-acylation of the spike protein of human coronaviruses , 2020, bioRxiv.

[2]  H. Yao,et al.  A peptidic inhibitor for PD-1 palmitoylation targets its expression and functions , 2020, RSC chemical biology.

[3]  H. Hang,et al.  Site-specific chemical fatty-acylation for gain-of-function analysis of protein S-palmitoylation in live cells. , 2020, Chemical communications.

[4]  X. Zou,et al.  A STAT3 palmitoylation cycle promotes TH17 differentiation and colitis , 2020, Nature.

[5]  Huiling Guo,et al.  CD36 facilitates fatty acid uptake by dynamic palmitoylation-regulated endocytosis , 2020, Nature Communications.

[6]  Rafal P. Wiewiora,et al.  Site-specific lipidation enhances IFITM3 membrane interactions and antiviral activity , 2020, bioRxiv.

[7]  P. Greengard,et al.  Innate immunity protein IFITM3 modulates γ-secretase in Alzheimer disease , 2020, Nature.

[8]  M. Diamond,et al.  IFITM3 functions as PIP3-scaffold to amplify PI3K signaling in B-cells , 2020, Nature.

[9]  L. Chamberlain,et al.  Regulatory effects of post-translational modifications on zDHHC S-acyltransferases , 2020, The Journal of Biological Chemistry.

[10]  E. Kudryashova,et al.  Opposing activities of IFITM proteins in SARS-CoV-2 infection , 2020, bioRxiv.

[11]  H. Mouquet,et al.  Syncytia formation by SARS‐CoV‐2‐infected cells , 2020, bioRxiv.

[12]  D. Fremont,et al.  Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion , 2020, Proceedings of the National Academy of Sciences.

[13]  J. Faraldo-Gómez,et al.  Structure and mechanism of DHHC protein acyltransferases. , 2020, Journal of molecular biology.

[14]  W. Wang,et al.  Viral and host factors related to the clinical outcome of COVID-19 , 2020, Nature.

[15]  Hanxin Lin,et al.  Bat SARS-Like WIV1 coronavirus uses the ACE2 of multiple animal species as receptor and evades IFITM3 restriction via TMPRSS2 activation of membrane fusion , 2020, Emerging microbes & infections.

[16]  E. Holmes,et al.  Bat IFITM3 restriction depends on S-palmitoylation and a polymorphic site within the CD225 domain , 2019, Life Science Alliance.

[17]  Temet M McMichael,et al.  Interferon-induced transmembrane proteins inhibit cell fusion mediated by trophoblast syncytins , 2019, The Journal of Biological Chemistry.

[18]  N. Warner,et al.  Palmitoylation of NOD1 and NOD2 is required for bacterial sensing , 2019, Science.

[19]  M. Fukata,et al.  ABHD10 is an S-depalmitoylase affecting redox homeostasis through peroxiredoxin-5 , 2019, Nature chemical biology.

[20]  B. Dickinson,et al.  Activity-Based Sensing of S-Depalmitoylases: Chemical Technologies and Biological Discovery. , 2019, Accounts of chemical research.

[21]  Timo Glatter,et al.  Palmitoylation is required for TNF-R1 signaling , 2019, Cell Communication and Signaling.

[22]  T. Heidmann,et al.  IFITM proteins inhibit placental syncytiotrophoblast formation and promote fetal demise , 2019, Science.

[23]  H. Yao,et al.  Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours , 2019, Nature Biomedical Engineering.

[24]  T. Taguchi,et al.  STING palmitoylation as a therapeutic target , 2019, Cellular & Molecular Immunology.

[25]  H. Hang,et al.  Peptidoglycan Metabolite Photoaffinity Reporters Reveal Direct Binding to Intracellular Pattern Recognition Receptors and Arf GTPases. , 2019, ACS chemical biology.

[26]  C. Rice,et al.  IFITM3 directly engages and shuttles incoming virus particles to lysosomes , 2019, Nature Chemical Biology.

[27]  Huiling Guo,et al.  DHHC4 and DHHC5 Facilitate Fatty Acid Uptake by Palmitoylating and Targeting CD36 to the Plasma Membrane. , 2019, Cell reports.

[28]  A. Brass,et al.  Interferon-induced transmembrane protein 3 blocks fusion of sensitive but not resistant viruses by partitioning into virus-carrying endosomes , 2019, PLoS pathogens.

[29]  M. Barenco,et al.  IFITM proteins drive type 2 T helper cell differentiation and exacerbate allergic airway inflammation , 2018, European journal of immunology.

[30]  S. Dixon,et al.  Protein palmitoylation and cancer , 2018, EMBO reports.

[31]  A. Thielke,et al.  Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling , 2018, Proceedings of the National Academy of Sciences.

[32]  G. Turcatti,et al.  Targeting STING with covalent small-molecule inhibitors , 2018, Nature.

[33]  Yang Sun,et al.  Protein Lipidation in Cell Signaling and Diseases: Function, Regulation, and Therapeutic Opportunities. , 2018, Cell chemical biology.

[34]  H. Molina,et al.  Selective Enrichment and Direct Analysis of Protein S-Palmitoylation Sites. , 2018, Journal of proteome research.

[35]  K. Kwiatkowska,et al.  Protein Palmitoylation and Its Role in Bacterial and Viral Infections , 2018, Front. Immunol..

[36]  A. Banerjee,et al.  Fatty acyl recognition and transfer by an integral membrane S-acyltransferase , 2018, Science.

[37]  Hening Lin,et al.  Protein Lipidation: Occurrence, Mechanisms, Biological Functions, and Enabling Technologies. , 2018, Chemical reviews.

[38]  Sang Joon Won,et al.  Protein depalmitoylases , 2018, Critical reviews in biochemistry and molecular biology.

[39]  Jinhong Chang,et al.  Identification of Residues Controlling Restriction versus Enhancing Activities of IFITM Proteins on Entry of Human Coronaviruses , 2017, Journal of Virology.

[40]  T. Ijuin,et al.  DHHC5-mediated palmitoylation of S1P receptor subtype 1 determines G-protein coupling , 2017, Scientific Reports.

[41]  H. Hang,et al.  The palmitoyltransferase ZDHHC20 enhances interferon-induced transmembrane protein 3 (IFITM3) palmitoylation and antiviral activity , 2017, The Journal of Biological Chemistry.

[42]  O. Schwartz,et al.  IFITM3 requires an amphipathic helix for antiviral activity , 2017, EMBO reports.

[43]  Mingzi M. Zhang,et al.  Protein S-palmitoylation in cellular differentiation , 2017, Biochemical Society transactions.

[44]  R. Norton,et al.  Selenoprotein K regulation of palmitoylation and calpain cleavage of ASAP2 is required for efficient FcγR‐mediated phagocytosis , 2017, Journal of leukocyte biology.

[45]  B. Dickinson,et al.  A fluorescent probe for cysteine depalmitoylation reveals dynamic APT signaling , 2016, Nature chemical biology.

[46]  G. Barber,et al.  Activation of STING requires palmitoylation at the Golgi , 2016, Nature Communications.

[47]  M. Fukata,et al.  Identification of PSD-95 Depalmitoylating Enzymes , 2016, The Journal of Neuroscience.

[48]  A. Brass,et al.  The IFITMs Inhibit Zika Virus Replication. , 2016, Cell reports.

[49]  H. Hang,et al.  Mass-tag labeling reveals site-specific and endogenous levels of protein S-fatty acylation , 2016, Proceedings of the National Academy of Sciences.

[50]  Matthew R. Pratt,et al.  Chemical Methods for Encoding and Decoding of Posttranslational Modifications. , 2016, Cell chemical biology.

[51]  E. Conibear,et al.  ABHD17 proteins are novel protein depalmitoylases that regulate N-Ras palmitate turnover and subcellular localization , 2015, eLife.

[52]  S. Kliche,et al.  Quantitative analysis of the human T cell palmitome , 2015, Scientific Reports.

[53]  Nicholas M. Chesarino,et al.  IFITMs from Mycobacteria Confer Resistance to Influenza Virus When Expressed in Human Cells , 2015, Viruses.

[54]  M. Shipston,et al.  The physiology of protein S-acylation. , 2015, Physiological reviews.

[55]  H. Hang,et al.  Chemical reporters for exploring protein acylation. , 2015, Biochemical Society transactions.

[56]  I. Lossos,et al.  HGAL localization to cell membrane regulates B-cell receptor signaling. , 2015, Blood.

[57]  H. Hang,et al.  Bifunctional fatty acid chemical reporter for analyzing S-palmitoylated membrane protein-protein interactions in mammalian cells. , 2015, Journal of the American Chemical Society.

[58]  Murugesan V. S. Rajaram,et al.  Chemoproteomics reveals Toll-like receptor fatty acylation , 2014, BMC Biology.

[59]  J. Durivault,et al.  Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability , 2014, Cell Death and Differentiation.

[60]  Fei Liu,et al.  Interferon induction of IFITM proteins promotes infection by human coronavirus OC43 , 2014, Proceedings of the National Academy of Sciences.

[61]  R. Hannoush,et al.  Method for cellular imaging of palmitoylated proteins with clickable probes and proximity ligation applied to Hedgehog, tubulin, and Ras. , 2014, Journal of the American Chemical Society.

[62]  A. Brass,et al.  IFITMs Restrict the Replication of Multiple Pathogenic Viruses , 2013, Journal of Molecular Biology.

[63]  Nicholas M. Chesarino,et al.  Palmitoylation on Conserved and Nonconserved Cysteines of Murine IFITM1 Regulates Its Stability and Anti-Influenza A Virus Activity , 2013, Journal of Virology.

[64]  M. Resh.  Covalent lipid modifications of proteins , 2013, Current Biology.

[65]  Mehul M. Vora,et al.  The CD225 Domain of IFITM3 Is Required for both IFITM Protein Association and Inhibition of Influenza A Virus and Dengue Virus Replication , 2013, Journal of Virology.

[66]  C. Haass,et al.  Palmitoylation of TNF alpha is involved in the regulation of TNF receptor 1 signalling. , 2013, Biochimica et biophysica acta.

[67]  Mingzi M. Zhang,et al.  Emerging roles for protein S-palmitoylation in immunity from chemical proteomics. , 2013, Current opinion in chemical biology.

[68]  Brent R. Martin,et al.  Profiling and inhibiting reversible palmitoylation. , 2013, Current opinion in chemical biology.

[69]  J. Mintern,et al.  Enhanced survival of lung tissue-resident memory CD8+ T cells during infection with influenza virus due to selective expression of IFITM3 , 2013, Nature Immunology.

[70]  U. Jhala,et al.  Proteomic analysis of protein palmitoylation in adipocytes , 2013, Adipocyte.

[71]  Jyoti S. Choudhary,et al.  Analysis of Protein Palmitoylation Reveals a Pervasive Role in Plasmodium Development and Pathogenesis , 2012, Cell host & microbe.

[72]  Jérôme Garin,et al.  Proteomic Analysis of S-Acylated Proteins in Human B Cells Reveals Palmitoylation of the Immune Regulators CD20 and CD23 , 2012, PloS one.

[73]  A. Sikorski,et al.  Human DHHC proteins: a spotlight on the hidden player of palmitoylation. , 2012, European journal of cell biology.

[74]  Benjamin F. Cravatt,et al.  Global profiling of dynamic protein palmitoylation , 2011, Nature Methods.

[75]  H. Hang,et al.  Exploring protein lipidation with chemical biology. , 2011, Chemical reviews.

[76]  J. Greaves,et al.  DHHC palmitoyl transferases: substrate interactions and (patho)physiology. , 2011, Trends in biochemical sciences.

[77]  G. Charron,et al.  Differential Regulation of Two Palmitoylation Sites in the Cytoplasmic Tail of the β1-Adrenergic Receptor* , 2011, The Journal of Biological Chemistry.

[78]  G. Charron,et al.  Proteomic Analysis of Fatty-acylated Proteins in Mammalian Cells with Chemical Reporters Reveals S-Acylation of Histone H3 Variants , 2011, Molecular & Cellular Proteomics.

[79]  Rainbo Hultman,et al.  Site-specific analysis of protein S-acylation by resin-assisted capture[S] , 2011, Journal of Lipid Research.

[80]  D. Marguet,et al.  Palmitoylation of human FasL modulates its cell death-inducing function , 2010, Cell Death and Disease.

[81]  G. Charron,et al.  Palmitoylome profiling reveals S-palmitoylation-dependent antiviral activity of IFITM3. , 2010, Nature chemical biology.

[82]  Stefan Wetzel,et al.  Small-molecule inhibition of APT1 affects Ras localization and signaling. , 2010, Nature chemical biology.

[83]  Mingzi M. Zhang,et al.  Tandem fluorescence imaging of dynamic S-acylation and protein turnover , 2010, Proceedings of the National Academy of Sciences.

[84]  S. Yalovsky,et al.  Analysis of protein S-acylation by gas chromatography–coupled mass spectrometry using purified proteins , 2010, Nature Protocols.

[85]  L. Andĕra,et al.  Functional analysis of the posttranslational modifications of the death receptor 6. , 2009, Biochimica et biophysica acta.

[86]  A. Passarelli,et al.  Mutation of juxtamembrane cysteines in the tetraspanin CD81 affects palmitoylation and alters interaction with other proteins at the cell surface. , 2009, Experimental cell research.

[87]  F. Abdel-Sater,et al.  Palmitoylation of the TRAIL receptor DR4 confers an efficient TRAIL-induced cell death signalling. , 2009, The Biochemical journal.

[88]  Mingzi M. Zhang,et al.  Robust fluorescent detection of protein fatty-acylation with chemical reporters. , 2009, Journal of the American Chemical Society.

[89]  Brent R. Martin,et al.  Large-scale profiling of protein palmitoylation in mammalian cells , 2009, Nature Methods.

[90]  John R. Yates,et al.  Neural Palmitoyl-Proteomics Reveals Dynamic Synaptic Palmitoylation , 2008, Nature.

[91]  A. Bailey,et al.  Palmitoylated proteins: purification and identification , 2007, Nature Protocols.

[92]  M. Peter,et al.  Palmitoylation of CD95 facilitates formation of SDS‐stable receptor aggregates that initiate apoptosis signaling , 2007, The EMBO journal.

[93]  J. Yates,et al.  Global Analysis of Protein Palmitoylation in Yeast , 2006, Cell.

[94]  M. Fukata,et al.  Impaired activation and localization of LAT in anergic T cells as a consequence of a selective palmitoylation defect. , 2006, Immunity.

[95]  H. Trist,et al.  Raft localisation of FcgammaRIIa and efficient signaling are dependent on palmitoylation of cysteine 208. , 2006, Immunology letters.

[96]  K. Miyake,et al.  Palmitoylation of LAT contributes to its subcellular localization and stability. , 2006, Biochemical and biophysical research communications.

[97]  Deborah A. Brown,et al.  Palmitoylation and Intracellular Domain Interactions Both Contribute to Raft Targeting of Linker for Activation of T Cells* , 2005, Journal of Biological Chemistry.

[98]  Herbert Waldmann,et al.  An Acylation Cycle Regulates Localization and Activity of Palmitoylated Ras Isoforms , 2005, Science.

[99]  W. Bornmann,et al.  B Cell Signaling Is Regulated by Induced Palmitoylation of CD81* , 2004, Journal of Biological Chemistry.

[100]  J. Brogdon,et al.  CD4 Raft Association and Signaling Regulate Molecular Clustering at the Immunological Synapse Site1 , 2004, The Journal of Immunology.

[101]  R. Deschenes,et al.  Identification of a Ras Palmitoyltransferase in Saccharomyces cerevisiae * , 2002, The Journal of Biological Chemistry.

[102]  Linyi Chen,et al.  The yeast DHHC cysteine-rich domain protein Akr1p is a palmitoyl transferase , 2002, The Journal of cell biology.

[103]  R. Doms,et al.  Palmitoylation of CCR5 Is Critical for Receptor Trafficking and Efficient Activation of Intracellular Signaling Pathways* , 2001, The Journal of Biological Chemistry.

[104]  K. Tanaka,et al.  Transmembrane TNF (pro‐TNF) is palmitoylated , 2001, FEBS letters.

[105]  T. Hamaoka,et al.  A pivotal role of cysteine 3 of Lck tyrosine kinase for localization to glycolipid-enriched microdomains and T cell activation. , 2001, Immunology letters.

[106]  T. Harder,et al.  Selective Accumulation of Raft-Associated Membrane Protein Lat in T Cell Receptor Signaling Assemblies , 2000, The Journal of cell biology.

[107]  E. Palmer,et al.  Essential Role of CD8 Palmitoylation in CD8 Coreceptor Function1 , 2000, The Journal of Immunology.

[108]  A. Gilman,et al.  A Cytoplasmic Acyl-Protein Thioesterase That Removes Palmitate from G Protein α Subunits and p21RAS * , 1998, The Journal of Biological Chemistry.

[109]  S. Ley,et al.  S‐acylation of LCK protein tyrosine kinase is essential for its signalling function in T lymphocytes , 1997, The EMBO journal.

[110]  M. Resh,et al.  Palmitoylation of p59fyn is reversible and sufficient for plasma membrane association. , 1997, Molecular biology of the cell.

[111]  B. Sefton,et al.  Palmitoylation of either Cys-3 or Cys-5 is required for the biological activity of the Lck tyrosine protein kinase , 1995, Molecular and cellular biology.

[112]  L. Peltonen,et al.  Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis , 1995, Nature.

[113]  M. Resh,et al.  Myristylation and palmitylation of Src family members: The fats of the matter , 1994, Cell.

[114]  B. Crise,et al.  Identification of palmitoylation sites on CD4, the human immunodeficiency virus receptor. , 1992, The Journal of biological chemistry.

[115]  F. G. van der Goot,et al.  SwissPalm 2: Protein S-Palmitoylation Database. , 2019, Methods in molecular biology.

[116]  H. Hang,et al.  Chemical Proteomic Profiling of Protein Fatty-Acylation in Microbial Pathogens. , 2019, Current topics in microbiology and immunology.

[117]  Brent R. Martin,et al.  Dynamic palmitoylation and the role of DHHC proteins in T cell activation and anergy. , 2011, Advances in immunology.

[118]  R. Deschenes,et al.  Palmitoylation: policing protein stability and traffic , 2007, Nature Reviews Molecular Cell Biology.

[119]  M. Marsh,et al.  The on-off story of protein palmitoylation. , 2003, Trends in cell biology.