Deubiquitinase MYSM1 Regulates Innate Immunity through Inactivation of TRAF3 and TRAF6 Complexes

Swarupa Panda; Jonas A Nilsson; Nelson O Gekara

doi:10.1016/j.immuni.2015.09.010

Deubiquitinase MYSM1 Regulates Innate Immunity through Inactivation of TRAF3 and TRAF6 Complexes

Immunity. 2015 Oct 20;43(4):647-59. doi: 10.1016/j.immuni.2015.09.010.

Authors

Swarupa Panda¹, Jonas A Nilsson², Nelson O Gekara³

Affiliations

¹ 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.
² Sahlgrenska Cancer Center, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, 41390, Gothenburg, Sweden.
³ 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.

PMID: 26474655
DOI: 10.1016/j.immuni.2015.09.010

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cytoplasm / metabolism
Disease Susceptibility
Endopeptidases / chemistry
Endopeptidases / deficiency
Endopeptidases / genetics
Endopeptidases / immunology*
Gene Expression Regulation / immunology
Immunity, Innate / immunology*
Infections / immunology*
Inflammation / immunology*
Interferon Type I / immunology
Listeria monocytogenes / immunology
Listeriosis / immunology
Mice
Mice, Transgenic
Models, Immunological
Proteasome Endopeptidase Complex
Protein Interaction Mapping
Protein Structure, Tertiary
Proteolysis
RAW 264.7 Cells
RNA Interference
RNA, Small Interfering / genetics
Receptors, Pattern Recognition / immunology
Shock, Septic / immunology
TNF Receptor-Associated Factor 3 / antagonists & inhibitors*
TNF Receptor-Associated Factor 3 / chemistry
TNF Receptor-Associated Factor 6 / antagonists & inhibitors*
TNF Receptor-Associated Factor 6 / chemistry
Trans-Activators
Transfection
Ubiquitin-Specific Proteases
Ubiquitination
Vesicular Stomatitis / immunology
Vesiculovirus / immunology

Substances

Interferon Type I
RNA, Small Interfering
Receptors, Pattern Recognition
TNF Receptor-Associated Factor 3
TNF Receptor-Associated Factor 6
Trans-Activators
Endopeptidases
MYSM1 protein, mouse
Ubiquitin-Specific Proteases
Proteasome Endopeptidase Complex