title: Deubiquitinase MYSM1 Regulates Innate Immunity through Inactivation of TRAF3 and TRAF6 Complexes.
abstract: Pattern-recognition receptors (PRRs) including Toll-like receptors, RIG-I-like receptors, and cytoplasmic DNA receptors are essential for protection against pathogens but require tight control to avert inflammatory diseases. The mechanisms underlying this strict regulation are unclear. MYSM1 was previously described as a key component of epigenetic signaling machinery. We found that in response to microbial stimuli, MYSM1 accumulated in the cytoplasm where it interacted with and inactivated TRAF3 and TRAF6 complexes to terminate PRR pathways for pro-inflammatory and type I interferon responses. Consequently, Mysm1 deficiency in mice resulted in hyper-inflammation and enhanced viral clearance but also susceptibility to septic shock. We identified two motifs in MYSM1 that were essential for innate immune suppression: the SWIRM domain that interacted with TRAF3 and TRAF6 and the metalloproteinase domain that removed K63 polyubiquitins. This study identifies MYSM1 as a key negative regulator of the innate immune system that guards against an overzealous self-destructive immune response.
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, 90 187, Umeå, Sweden; Department of Molecular Biology, Umeå University, 90 187, Umeå, Sweden; Umeå Centre for Microbial Research (UCMR), Umeå University, 90 187, Umeå, Sweden.
authors.forename: Swarupa
authors.initials: S
authors.lastname: Panda
authors.affiliation: Sahlgrenska Cancer Center, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, 41390, Gothenburg, Sweden.
authors.forename: Jonas A
authors.initials: JA
authors.lastname: Nilsson
authors.affiliation: Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, 90 187, Umeå, Sweden; Department of Molecular Biology, Umeå University, 90 187, Umeå, Sweden; Umeå Centre for Microbial Research (UCMR), Umeå University, 90 187, Umeå, Sweden. Electronic address: nelson.gekara@mims.umu.se.
authors.forename: Nelson O
authors.initials: NO
authors.lastname: Gekara
mesh_terms: D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D004198:Disease Susceptibility; D010450:Endopeptidases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology*; D007239:Infections / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D018448:Models, Immunological; D046988:Proteasome Endopeptidase Complex; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D000067996:RAW 264.7 Cells; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051192:Receptors, Pattern Recognition / Q000276:immunology; D012772:Shock, Septic / Q000276:immunology; D048008:TNF Receptor-Associated Factor 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D048029:TNF Receptor-Associated Factor 6 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015534:Trans-Activators; D014162:Transfection; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination; D054243:Vesicular Stomatitis / Q000276:immunology; D018116:Vesiculovirus / Q000276:immunology
chemical_list: D007370:Interferon Type I; D034741:RNA, Small Interfering; D051192:Receptors, Pattern Recognition; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; D015534:Trans-Activators; D010450:Endopeptidases; C570173:MYSM1 protein, mouse; D064570:Ubiquitin-Specific Proteases; D046988:Proteasome Endopeptidase Complex