@article{bae99a6fcfe44b0cba9dc8f32ba89ff4,
title = "Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type i interferons and proinflammatory cytokines",
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.",
author = "Tseng, {Ping Hui} and Atsushi Matsuzawa and Weizhou Zhang and Takashi Mino and Vignali, {Dario A.A.} and Michael Karin",
note = "Funding Information: We thank H. Ichijo (University of Tokyo) for providing A.M. with space and support for some of this work described above; S. Akira (Osaka University) for Myd88−/− mice; B. Beutler (Scripps Research Institute) for TrifLps2/Lps2 mice; R. Fonseca (Mayo Clinic) for multiple myeloma cells; X. Wang (University of Texas Southwestern Medical Center) for SM; H. Wang (St. Jude Children{\textquoteright}s Research Hospital) for generating monoclonal antibody HWA4C4, specific for K63linked ubiquitin; I. Verma (Salk Institute) for pLVCMVdelta 8.2; and Millipore for the antibody to K48linked polyubiquitin. Supported by the National Institutes of Health (AI043477 to M.K. and AI52199 to D.A.A.V.), the American Cancer Society (M.K.), the American Lung Association of California (P.H.T.), the Global Center of Excellence program (A.M.), the Toyobo Biotechnology Foundation (T.M.), the National Cancer Institute (CA21765 to D.A.A.V.) and the American Lebanese Syrian Associated Charities (D.A.A.V.).",
year = "2010",
month = jan,
doi = "10.1038/ni.1819",
language = "English",
volume = "11",
pages = "70--75",
journal = "Nature Immunology",
issn = "1529-2908",
number = "1",
}