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PMID: 27893701 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The signaling adaptor TRAF1 negatively regulates Toll-like receptor signaling and this underlies its role in rheumatic disease.

Nature immunology ·Vol. 18 ·No. 1 ·2017-00-00 ·Pages 26-35

Abdul-Sater AA, Edilova MI, Clouthier DL, Mbanwi A, Kremmer E, Watts TH

Abstract

TRAF1 is a signaling adaptor known for its role in tumor necrosis factor receptor-induced cell survival. Here we show that monocytes from healthy human subjects with a rheumatoid arthritis-associated single-nucleotide polymorphism (SNP) in the TRAF1 gene express less TRAF1 protein but greater amounts of inflammatory cytokines in response to lipopolysaccharide (LPS). The TRAF1 MATH domain binds directly to three components of the linear ubiquitination (LUBAC) complex, SHARPIN, HOIP and HOIL-1, to interfere with the recruitment and linear ubiquitination of NEMO. This results in decreased NF-κB activation and cytokine production, independently of tumor necrosis factor. Consistent with this, Traf1-/- mice show increased susceptibility to LPS-induced septic shock. These findings reveal an unexpected role for TRAF1 in negatively regulating Toll-like receptor signaling, providing a mechanistic explanation for the increased inflammation seen with a disease-associated TRAF1 SNP.

MeSH Terms
Animals Arthritis, Rheumatoid/genetics Cytokines/metabolism Genetic Predisposition to Disease HEK293 Cells Humans Inflammation Mediators/metabolism Leukocytes, Mononuclear/immunology Lipopolysaccharides/immunology Mice Mice, Inbred C57BL Mice, Knockout Monocytes/immunology Polymorphism, Single Nucleotide RNA, Small Interfering/genetics Signal Transduction/genetics TNF Receptor-Associated Factor 1/genetics,metabolism Toll-Like Receptors/metabolism
Chemicals
Cytokines Inflammation Mediators Lipopolysaccharides RNA, Small Interfering TNF Receptor-Associated Factor 1 Toll-Like Receptors
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Abdul-Sater Ali A
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Edilova Maria I
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Clouthier Derek L
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Mbanwi Achire
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Kremmer Elisabeth
Institut für Molekulare Immunologie, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), München, Germany.
Watts Tania H ORCID
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
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Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.3618
Published
2017-00-00
Epub
2016-00-28
Pages
26-35
Language
English
Region
United States
NLM ID
100941354
Subset
IM
Grants
CIHR · MOP-74492 · Canada
CIHR · FDN-143250 · Canada
Corrections
CommentIn
PMID: 27928155
External Links
PubMed source DOI: 10.1038/ni.3618 View journal details
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