Journal
NATURE IMMUNOLOGY
Volume 17, Issue 2, Pages 140-149Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.3342
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Funding
- Institut National du Cancer [PLBIO13-057]
- Agence Nationale de la Recherche [ANR-14-CE16]
- Ligue Nationale Contre le Cancer (Equipes labellisees)
- Fondation pour la Recherche Medicale (FRM) [AJE201212]
- Region-Midi-Pyrenees [NVEQ 2014]
- European Research Council ('SUMOSTRESS')
- European Research Council ('HIVINNATE') [309848]
- European Research Council [DC-BIOX340046]
- Ecole Normale Superieure
- Odyssey-RE
- European Research Council (ERC) [309848] Funding Source: European Research Council (ERC)
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Innate sensing of pathogens initiates inflammatory cytokine responses that need to be tightly controlled. We found here that after engagement of Toll-like receptors (TLRs) in myeloid cells, deficient sumoylation caused increased secretion of transcription factor NF-kappa B-dependent inflammatory cytokines and a massive type I interferon signature. In mice, diminished sumoylation conferred susceptibility to endotoxin shock and resistance to viral infection. Overproduction of several NF-kappa B-dependent inflammatory cytokines required expression of the type I interferon receptor, which identified type I interferon as a central sumoylation-controlled hub for inflammation. Mechanistically, the small ubiquitin-like modifier SUMO operated from a distal enhancer of the gene encoding interferon-beta (Ifnb1) to silence both basal and stimulus-induced activity of the Ifnb1 promoter. Therefore, sumoylation restrained inflammation by silencing Ifnb1 expression and by strictly suppressing an unanticipated priming by type I interferons of the TLR-induced production of inflammatory cytokines.
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