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

作者：Tseng Ping Hui; Matsuzawa Atsushi; Zhang Weizhou; Mino Takashi; Vignali Dario A A; Karin Michael^*

来源：Nature Immunology, 2010, 11(1): 70-1819.

DOI：10.1038/ni.1819

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.

• 出版日期2010-1