Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type i interferons and proinflammatory cytokines

Ping Hui Tseng, Atsushi Matsuzawa, Weizhou Zhang, Takashi Mino, Dario A.A. Vignali, Michael Karin

Research output: Contribution to journalArticlepeer-review

286 Citations (Scopus)

Abstract

Balanced production of type I interferons and proinflammatory cytokines after engagement of Toll-like receptors (TLRs), which signal through adaptors containing a Toll-interleukin 1 receptor (TIR) domain, such as MyD88 and TRIF, has been proposed to control the pathogenesis of autoimmune disease and tumor responses to inflammation. Here we show that TRAF3, a ubiquitin ligase that interacts with both MyD88 and TRIF, regulated the production of interferon and proinflammatory cytokines in different ways. Degradative ubiquitination of TRAF3 during MyD88-dependent TLR signaling was essential for the activation of mitogen-activated protein kinases (MAPKs) and production of inflammatory cytokines. In contrast, TRIF-dependent signaling triggered noncanonical TRAF3 self-ubiquitination that activated the interferon response. Inhibition of degradative ubiquitination of TRAF3 prevented the expression of all proinflammatory cytokines without affecting the interferon response.

Original languageEnglish
Pages (from-to)70-75
Number of pages6
JournalNature Immunology
Volume11
Issue number1
DOIs
Publication statusPublished - 2010 Jan
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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