A functional C-terminal TRAF3-binding site in MAVS participates in positive and negative regulation of the IFN antiviral response

Paz, Suzanne; Vilasco, Myriam; Werden, Steven J.; Arguello, Meztli; Joseph-Pillai, Deshanthe; Zhao, Tiejun; Nguyên, Thi Lien-Anh; Sun, Qiang; Meurs, Éliane; Lin, Rongtuan; Hiscott, John

doi:10.1038/cr.2011.2

Cited by 134 publications

(128 citation statements)

References 73 publications

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“…In addition, Triad3A could target TRAF3 for Lys 48 -linked ubiquitin-mediated degradation, and negatively regulate the RIG-I/MAVS signals. Two amino acids in the TRAF domain of TRAF3, Y440 and Q442, are reported to be pivotal for TRAF3 to bind MAVS (19,26). However, the data presented show that the two amino acids, Y440 and Q442, are dispensable for TRAF3 to bind UXT-V1.…”

Section: /2contrasting

confidence: 51%

“…Interestingly, a recent study also characterized that the TRAF domain was responsible for binding MAVS. In particular, two amino acids, Y440 and Q442, in this TRAF domain were critical for TRAF3 to interact with MAVS (19,26). So, we tested whether these two amino acids were also critical for TRAF3 to bind UXT-V1.…”

Section: Uxt-v1 Facilitates the Interaction Between Traf3 And Mavsmentioning

confidence: 99%

“…A TRAF-binding motif (455-PEENEY-460) has been identified in MAVS. Mutating this motif abolishes the ability of MAVS to interact with TRAF3 and cripples the MAVS-dependent IFN production (26). Conversely, mutating the Y440 and Q442 of TRAF3 attenuates its binding to MAVS (19,27).…”

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confidence: 99%

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UXT-V1 Facilitates the Formation of MAVS Antiviral Signalosome on Mitochondria

Huang

Liu

et al. 2012

The Journal of Immunology

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Virus infection induces the MAVS–TNFR-associated factor (TRAF) 3 signaling axis on mitochondria. It remains to elucidate the corresponding regulatory processes. In this study, we identify UXT-V1 as a novel TRAF3-binding protein. UXT-V1 is critical for the virus-induced activation of NF-κB and IFN regulatory factor 3. Reduction of UXT-V1 impairs the induction of IFN-β and attenuates the host antiviral responses. The N-terminal TRAF-binding motif of UXT-V1 binds to the C-terminal TRAF domain of TRAF3, thus facilitating the interaction between TRAF3 and MAVS. Notably, TRAF3 and TNFR-associated death domain protein are recruited onto mitochondria upon virus infection. These translocations are blocked when knocking down UXT-V1. Thus, UXT-V1 represents a novel integral component of the MAVS signalosome on mitochondria, mediating the innate antiviral signal transduction.

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Section: /2contrasting

confidence: 51%

Section: Uxt-v1 Facilitates the Interaction Between Traf3 And Mavsmentioning

confidence: 99%

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UXT-V1 Facilitates the Formation of MAVS Antiviral Signalosome on Mitochondria

Huang

Liu

et al. 2012

The Journal of Immunology

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“…Recently, several proteins (Tom70, TRAF2/3/5/6, and TRADD) are characterized to perform functions in MAVS (5,8,9,22,37). Notably, it remains to elucidate how MAVS directly links to the critical protein kinase TBK1 and understand the detailed mechanism of signal transduction.…”

Section: Discussionmentioning

confidence: 99%

IFN-Induced TPR Protein IFIT3 Potentiates Antiviral Signaling by Bridging MAVS and TBK1

Liu

Chen

Wei

et al. 2011

The Journal of Immunology

156

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Intracellular RNA viruses are sensed by receptors retinoic acid-inducible gene I/MDA5, which trigger formation of the mitochondrial antiviral signaling (MAVS) complex on mitochondria. Consequently, this leads to the activation of TNFR-associated factor family member-associated NF-κB activator-binding kinase 1 (TBK1) and phosphorylation of IFN regulatory factor 3 (IRF3). It remains to be elucidated how MAVS activates TBK1/IRF3. In this study, we report that IFN-induced protein with tetratricopeptide repeats 3 (IFIT3) is significantly induced upon RNA virus infection. Ectopic expression or knockdown of IFIT3 could, respectively, enhance or impair IRF3-mediated gene expression. Mechanistically, the tetratrico-peptide repeat motif (E164/E165) of IFIT3 interacts with the N terminus (K38) of TBK1, thus bridging TBK1 to MAVS on the mitochondrion. Disruption of this interaction markedly attenuates the activation of TBK1 and IRF3. Furthermore, host antiviral responses are significantly boosted or crippled in the presence or absence of IFIT3. Collectively, our study characterizes IFIT3 as an important modulator in innate immunity, revealing a new function of the IFIT family proteins (IFN-induced protein with tetratricopeptide repeats).

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“…It remains unclear why these filaments are potent inducers of downstream signaling; however, RLR cascade proteins including NEMO, IKKε, and various TRAFs possess MAVS-targeting signals (Paz et al, 2011). Furthermore, TBK1 and other key RLR cascade proteins interact with these proteins but are activated only upon oligomerization.…”

Section: Convergence At Mavsmentioning

confidence: 99%