TRAF3IP3 negatively regulates cytosolic RNA induced anti-viral signaling by promoting TBK1 K48 ubiquitination

Abstract

Innate immunity to nucleic acids forms the backbone for anti-viral immunity and several inflammatory diseases. Upon sensing cytosolic viral RNA, retinoic acid-inducible gene-I-like receptors (RLRs) interact with the mitochondrial antiviral signaling protein (MAVS) and activate TANK-binding kinase 1 (TBK1) to induce type I interferon (IFN-I). TRAF3-interacting protein 3 (TRAF3IP3, T3JAM) is essential for T and B cell development. It is also wellexpressed by myeloid cells, where its role is unknown. Here we report that TRAF3IP3 suppresses cytosolic poly(I:C), 5'ppp-dsRNA, and vesicular stomatitis virus (VSV) triggers IFN-I expression in overexpression systems and Traf3ip3 −/− primary myeloid cells. The mechanism of action is through the interaction of TRAF3IP3 with endogenous TRAF3 and TBK1. This leads to the degradative K48 ubiquitination of TBK1 via its K372 residue in a DTX4-dependent fashion. Mice with myeloid-specific gene deletion of Traf3ip3 have increased RNA virus-triggered IFN-I production and reduced susceptibility to virus. These results identify a function of TRAF3IP3 in the regulation of the host response to cytosolic viral RNA in myeloid cells.

SARS-CoV-2 Membrane Protein Inhibits Type I Interferon Production Through Ubiquitin-Mediated Degradation of TBK1

“…For example, both SARS-CoV N and SARS-CoV-2 PLpro-TM proteins inhibit TRIM25-mediated K63-linked ubiquitination of RIG-I and suppress innate immune response ( 37 , 38 ). Several deubiquitinating enzymes and E3 ubiquitin ligases have been shown to regulate the ubiquitin level of TBK1 and participate in innate immune response during virus infection ( 36 , 39 , 40 ). TRIM27 has been reported to interact and degrade TBK1 via K48-linked ubiquitination ( 39 ).…”

Functions and Molecular Mechanisms of Deltex Family Ubiquitin E3 Ligases in Development and Disease

“…The Ub-specific protease 38 (USP38), TRAF-interacting protein (TRIP), Nod-like receptor (NLR) family pyrin domain containing 4 (NLRP4), and DTX4 complex polyubiquitinates TBK1, thereby degrading it to limit the virus-induced IFN-I signaling pathway ( Cui et al, 2012 ). Some interacting proteins, such as TNF receptor-associated factor 3-interacting protein 3 (TRAF3IP3) and dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 2 (DYRK2), are also essential for the NLRP4/DTX4 complex to promote TBK1 degradation via Lys48-linked ubiquitination ( An et al, 2015 ; Deng et al, 2020 ). In chronic hepatitis B, the reduction of DTX4 expression partially mediates the IFN-I signaling pathway to increase the sustenance of hepatitis B virus (HBV) and maintenance of hepatitis B surface antigen (HBsAg) in the serum ( Kim et al, 2018 ).…”

Negative Regulation of the Innate Immune Response through Proteasomal Degradation and Deubiquitination

“…ZNRF4 [195] ITCH [336] (indirectly) A20 [187] OTULIN [185] CYLD [190] MYSM1 [193] LUBAC (E3 ligase) OTULIN [188,189,191] TBK1 DTX4 [113][114][115] TRAIP [116] TRIM27 [118] SOCS3 [337] TRIM11 [338] RNF144B [339] ASB8 [340] CYLD [67] USP38 [117] USP2b [341] A20 [110,342] TAK1 USP18 [343] TAB2/3 TRIM30α [344] NEMO TRIM29 [244] TRAF7 [345] TRIM40 [346] TRAF4 [347] CYLD [218,220,223] A20 [210,348] USP18 [343] USP7 [349] UCHL1 [326] OTULIN [191] [8] SOCS1 [9] SOCS3 [9] NDRG1 [391] TRIM35+PIN1 [290] Unknown [288,299]…”

“…Recently, also TRAF3 Interacting Protein 3 (TRAF3IP3) was identified to recruit DTX4 to TBK1 and to promote TBK1 ubiquitination at K372 [115]. Traf3ip3-deficient BMDMs had decreased K48-ubiquitination of endogenous TBK1 in response to VSV infection, were more resistant to VSV infection, and had decreased viral titers due to increased IFNβ production [115]. In addition to promoting TBK1 degradation, TRAF3IP3 was shown to compete with MAVS for TRAF3 and TBK1 binding, thereby inhibiting downstream signaling [115].…”