Key Role of Ubc5 and Lysine-63 Polyubiquitination in Viral Activation of IRF3

Zeng, Wenwen; Xu, Ming; Liu, Siqi; Sun, Lijun; Chen, Zhijian J.

doi:10.1016/j.molcel.2009.09.037

Cited by 157 publications

(193 citation statements)

References 45 publications

(68 reference statements)

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“…Although it is strongly suggested that TRIM23 conjugates K27-type ubiquitin to NEMO, it remains further to analyze whether TRIM23 alone or TRIM23 together with other factor(s) exerts selecting activity of K27-type ubiquitin conjugation to NEMO. Recently, K63 type of ubiquitin was shown to be conjugated to NEMO upon VSV infection by in vitro ubiquitin conjugation analysis (31). However, this paper did not show the data that indicate lack of K63 ubiquitin conjugation in the lysate derived from uninfected cells.…”

Section: Discussionmentioning

confidence: 68%

Polyubiquitin conjugation to NEMO by triparite motif protein 23 (TRIM23) is critical in antiviral defense

Arimoto

Funami

Saeki

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

144

124

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The rapid induction of type I IFN is a central event of the innate defense against viral infections and is tightly regulated by a number of cellular molecules. Viral components induce strong type I IFN responses through the activation of toll-like receptors (TLRs) and intracellular cytoplasmic receptors such as an RNA helicase RIG-I and/ or MDA5. According to recent studies, the NF-κB essential modulator (NEMO, also called IKKγ) is crucial for this virus-induced antiviral response. However, the precise roles of signal activation by NEMO adaptor have not been elucidated. Here, we show that virus-induced IRF3 and NF-κB activation depends on the K(lys)-27-linked polyubiquitination to NEMO by the novel ubiquitin E3 ligase triparite motif protein 23 (TRIM23). Virus-induced IRF3 and NF-κB activation, as well as K27-linked NEMO polyubiquitination, were abrogated in TRIM23 knockdown cells, whereas TRIM23 knockdown had no effect on TNFα-mediated NF-κB activation. Furthermore, in NEMO-deficient mouse embryo fibroblast cells, IFN-stimulated response element-driven reporter activity was restored by ectopic expression of WT NEMO, as expected, but only partial recovery by NEMO K165/309/325/326/344R multipoints mutant on which TRIM23-mediated ubiquitin conjugation was substantially reduced. Thus, we conclude that TRIM23-mediated ubiquitin conjugation to NEMO is essential for TLR3-and RIG-I/MDA5-mediated antiviral innate and inflammatory responses.innate immunity | signal transduction | virus infection U pon viral infection, host cells recognize the viral components and activate innate immune signaling to exert antiviral responses (1-4). RIG-I and/or MDA5 sense viral dsRNA (5-8) and are recruited to another antiviral signaling adaptor, IPS-1 (also called MAVS, Cardif, or VISA) (9-12). IPS-1 directly interacts with TRAF3 and triggers auto-ubiquitination of TRAF3, which then activates TBK1 and IKKε, leading to activation of transcription factors NF-κB and IRF3 (13,14). A recent study indicated that NEMO acts upstream of TBK1 and IKKε and is essential for virus-induced TLR3-and RIG-I/MDA5-mediated antiviral activation (15).Because rapid induction of type I IFN expression is the key process in initiating the innate antiviral response, clarification of NEMO-mediated antiviral signaling is important for understanding innate immune signaling; however, NEMO-mediated antiviral signaling is not well elucidated. Recent studies indicate that several ubiquitin E3 ligases are involved in the regulation of innate immune signaling (16-21). We identified the ubiquitin E3 ligase TRIM23 (Triparite motif protein 23), also named ADP ribosylation factor domain protein 1 (ARD1), which was reported to have E3 ligase activity in vitro (22), that functioned as an E3 ligase for NEMO ubiquitin conjugation. TRIM23 exerts a potent antiviral state following its overexpression. Furthermore, we demonstrated that antiviral activity depends not on K(Lys)63-linked but on K27-linked polyubiquitin conjugation to multiple sites of NEMO by TRIM23 expression. Virus-in...

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Section: Discussionmentioning

confidence: 68%

Polyubiquitin conjugation to NEMO by triparite motif protein 23 (TRIM23) is critical in antiviral defense

Arimoto

Funami

Saeki

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

144

124

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“…NEMO mediates TBK1 activation by recruiting TBK1 to MAVS and eventually triggers IRF3 activation (5,10,11). In addition, NEMO is critical for activation of the canonical IKK complexes that control NF-κB activity (12).…”

mentioning

confidence: 99%

TRIM14 is a mitochondrial adaptor that facilitates retinoic acid-inducible gene-I–like receptor-mediated innate immune response

Zhou

Jia

Xue

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

117

116

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Innate immunity provides the first line of host defense against invading microbial pathogens. This defense involves retinoic acidinducible gene-I-like receptors that detect viral RNA and activate the mitochondrial antiviral-signaling (MAVS) protein, an adaptor protein, leading to activation of the innate antiviral immune response. The mechanisms by which the MAVS signalosome assembles on mitochondria are only partially understood. Here, we identify tripartite motif 14 (TRIM14) as a mediator in the immune response against viral infection. TRIM14 localizes to the outer membrane of mitochondria and interacts with MAVS. Upon viral infection, TRIM14 undergoes Lys-63-linked polyubiquitination at Lys-365 and recruits NF-κB essential modulator to the MAVS signalosome, leading to the activation of both the IFN regulatory factor 3 and NF-κB pathways. Knockdown of TRIM14 disrupts the association between NF-κB essential modulator and MAVS and attenuates the antiviral response. Our results indicate that TRIM14 is a component of the mitochondrial antiviral immunity that facilitates the immune response mediated by retinoic acidinducible gene-I-like receptors.A ctivation of the innate immune response involves the detection of pathogen-associated molecular patterns (PAMPs), such as microbial nucleic acids, proteins, lipids, and carbohydrates. PAMPs are recognized by cellular pattern recognition receptors (PRRs), including Toll-like receptors, retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), NOD-like receptors, and C-type lectin receptors. Upon recognition, PRRs trigger a series of signaling events that lead to the induction of type I IFNs and proinflammatory cytokines (1).RLRs such as RIG-I and melanoma differentiation-associated antigen 5 (MDA5) recognize cytosolic viral RNA (2). Upon binding of RNA to the helicase domain, RIG-I or MDA5 undergoes a conformational change (3) and is recruited to the mitochondrial antiviral signaling (MAVS) adaptor. After binding of RIG-1 or MAD5, MAVS recruits various downstream molecules and further activates two kinase complexes: the noncanonical IκB kinases (IKKs) [TANK-binding kinase 1 (TBK1)/IKKi] and the canonical IKK complexes comprised of IKKα, IKK-β, and NF-κB essential modulator (NEMO) (4, 5). The TBK1/IKKi kinases phosphorylate IFN regulatory factor 3/7 (IRF3/7), which translocates to the nucleus and drives the transcription of IFNs (6). The canonical IKKs phosphorylate IκBα, resulting in the ubiquitination and proteasomal degradation of IκBα. NF-κB then is released to the nucleus and stimulates the expression of proinflammatory genes (7).MAVS-deficient mice show abolished virus-triggered induction of IFNs and increased susceptibility to viral infection (8), indicating that MAVS is essential for the innate immune response. MAVS consists of an N-terminal caspase activation and recruitment domain, a proline-rich domain, and a C-terminal transmembrane domain that targets it to the mitochondrial outer membrane (9). It has been suggested that the mitochondrial outer membrane pr...

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“…K63-linked autoubiquitination at Lys124 is a key activation mechanism of TRAF6 (Lamothe et al, 2007;Jiao et al, 2015) and possibly TRAF2 (Habelhah et al, 2004), TRAF4 (Marinis et al, 2012), and TRAF5 (Zhong et al, 2012). In vitro TRAF3 ubiquitination assays and analysis of recombinant TRAF3ΔRI NG isolated from mammalian cell lysates are also consistent with an autoubiquitination activation mechanism for TRAF3 (Kayagaki et al, 2007;Zeng et al, 2009). …”

Section: Traf Ubiquitination Orients Immune Signal Transmissionmentioning

confidence: 53%