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 (IFN) and proinflammatory cytokines upon engagement of Toll-like receptors (TLRs), which signal via adaptors containing a Toll-IL-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, differentially regulated production of IFN and proinflammatory cytokines. Degradative TRAF3 ubiquitination during MyD88-dependent TLR signaling was essential for activation of mitogen-activated protein kinases (MAPKs) and inflammatory cytokine production. By contrast, TRIF-dependent signaling triggered non-canonical TRAF3 self-ubiquitination that activated the IFN response. Inhibition of degradative TRAF3 ubiquitination prevented expression of all proinflammatory cytokines without impacting the IFN response.

TAK1 control of cell death

“…4 Since this original finding, TAK1 also has been shown to be activated by a number of signaling molecules including cytokines such as TNFa and IL-1; ligands that interact with Toll-like receptors, B-cell receptor and T-cell receptor; and the lipotoxic molecule, ceramide. [5][6][7][8][9][10][11][12][13] Other endogenous death ligands of the TNF family, including TRAIL, also induce TAK1 activation. 14,15 Exogenous stressors and environmental changes such as osmotic stress, UV irradiation, ischemia and nutrient withdrawal activate TAK1.…”

Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K

“…Upon TLR4 stimulation, TRAF3 is modified by Lys 63-linked ubiquitination, which is required for subsequent activation of TANK-binding kinase 1 (TBK1) and IKKε. 53,54 Together, as UBE2N) and UEV1A (also known as UBE2V1), catalyzes the formation of Lys 63-linked polyubiquitin chains upon itself as well as free ubiquitin chains. 33 Synthesis of Lys 63-linked polyubiquitin chains by TRAF6 mediates recruitment of TAB2 and TAB3, which regulate the kinase TAK1, thus permitting TAK1 activity.…”

Ubiquitin in the activation and attenuation of innate antiviral immunity

“…Simultaneously, TRAF3 suppresses NF-κB by inhibiting IKK activation upon binding TRAF2 (Zarnegar et al, 2008), likely as a mechanism to skew innate immune effector molecule expression as required. Inversely, the E3 cIAP2, after itself being ubiquitinated by TRAF6, promotes TRAF3 degradation by ligating K48-linked polyubiquitin chains to TRAF3 at residues K107 and K156, thereby restoring NF-κB activation (Tseng et al, 2010). However, as well as degrading TRAF3, cIAP1/2 can also activate TRAF3 by catalyzing its K63-linked polyubiquitination ( Fig.…”

“…Activated TRAF6 ubiquitinates IRF7, leading to IFN-α expression (Kawai et al, 2004). TRAF6 also promotes K63-linked polyubiquitination of NEMO, enabling recruitment of the TGF-β-activated kinase (TAB)-TAK1 kinase complex (Tseng et al, 2010). Subsequent association between NEMO and M1-polyubiquitin chains induces TAK1-mediated phosphorylation of IKKα and IKKβ, priming them for full transactivation through autophosphorylation .…”

“…cIAP2 is an E3 that, after itself being ubiquitinated by TRAF6, targets TRAF3 for degradation (Tseng et al, 2010). This is important in promoting TLR4-mediated signaling and cytokine production at the expense of type I IFN production .…”