An autoinhibitory mechanism modulates MAVS activity in antiviral innate immune response

Shi, Yi; Yuan, Bofeng; Qi, Nan; Zhu, Wenting; Su, Jingru; Li, Xiaoyan; Qi, Peipei; Zhang, Dan; Hou, Fanfan

doi:10.1038/ncomms8811

Cited by 42 publications

(60 citation statements)

References 43 publications

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“…After electrophoresis in the running buffer (1 × TBE and 0.1% SDS) for 30 min with a constant voltage of 100 V at 4 °C, western immunoblotting was performed14.…”

Section: Methodsmentioning

confidence: 99%

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Ube2D3 and Ube2N are essential for RIG-I-mediated MAVS aggregation in antiviral innate immunity

et al. 2017

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Innate immunity plays a pivotal role in virus infection. RIG-I senses viral RNA and initiates an effective innate immune response for type I interferon production. To transduce RIG-I-mediated antiviral signalling, a mitochondrial protein MAVS forms prion-like aggregates to activate downstream kinases and transcription factors. However, the activation mechanism of RIG-I is incompletely understood. Here we identify two ubiquitin enzymes Ube2D3 and Ube2N through chromatographic purification as activators for RIG-I on virus infection. We show that together with ubiquitin ligase Riplet, Ube2D3 promotes covalent conjugation of polyubiquitin chains to RIG-I, while Ube2N preferentially facilitates production of unanchored polyubiquitin chains. In the presence of these polyubiquitin chains, RIG-I induces MAVS aggregation directly on the mitochondria. Our data thus reveal two essential polyubiquitin-mediated mechanisms underlying the activation of RIG-I and MAVS for triggering innate immune signalling in response to viral infection in cells.

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“…After electrophoresis in the running buffer (1 × TBE and 0.1% SDS) for 30 min with a constant voltage of 100 V at 4 °C, western immunoblotting was performed14.…”

Section: Methodsmentioning

confidence: 99%

“…On interaction with RIG-I 2CARD, MAVS forms prion-like filament and releases its active regions to recruit downstream signalling molecules1415. Notably, MAVS filament formation is a hallmark of its activation and essential for its antiviral function1516, highlighting the importance of the molecular mechanism underlying MAVS aggregation induced by RIG-I.…”

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confidence: 99%

Ube2D3 and Ube2N are essential for RIG-I-mediated MAVS aggregation in antiviral innate immunity

et al. 2017

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“…Accordingly, filamentous architecture of MAVS could play an additional role by further amplifying the clustering effect of TBK1 and IRF3. Furthermore, a recent study proposed a model where MAVS filament formation releases an auto-inhibition exerted by the cis inhibitory elements 53 . Although the precise nature of the auto-inhibition and the mechanism by which MAVS filament assembly releases the inhibition remain to be investigated, filament formation of MAVS appears to act at multiple steps for the signal activation.…”

Section: Rig-i-like Receptors (Rlrs): Rig-i and Mda5mentioning

confidence: 99%

Filament assemblies in foreign nucleic acid sensors

Sohn

Hur

2016

Current Opinion in Structural Biology

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Summary Helical filamentous assembly is ubiquitous in biology, but was only recently realized to be broadly employed in the innate immune system of vertebrates. Accumulating evidence suggests that the filamentous assemblies and helical oligomerization play important roles in detection of foreign nucleic acids and activation of the signaling pathways to produce antiviral and inflammatory mediators. In this review, we focus on the helical assemblies observed in the signaling pathways of RIG-I-like receptors (RLRs) and AIM2-like receptors (ALRs). We describe ligand-dependent oligomerization of receptor, receptor-dependent oligomerization of signaling adaptor molecules, and their functional implications and regulations.

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“…Various isoforms and N-terminal truncations of MAVS were cloned into pcDNA3-flag vector18. pcDNA-flag-mini-MAVS was constructed by ligation of MAVS CARD domain (aa-1–100) to TM domain (aa-511–540).…”

Section: Methodsmentioning

confidence: 99%

Multiple truncated isoforms of MAVS prevent its spontaneous aggregation in antiviral innate immune signalling

Shi

Zhang

et al. 2017

Nat Commun

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In response to virus infection, RIG-I-like receptors (RLRs) sense virus RNA and induce MAVS to form prion-like aggregates to further propagate antiviral signalling. Although monomeric MAVS recombinant protein can assemble into prion-like filaments spontaneously in vitro, endogenous MAVS in cells is prevented from aggregation until viral infection. The mechanism preventing cellular MAVS from spontaneous aggregation is unclear. Here we show that multiple N-terminal truncated isoforms of MAVS are essential in preventing full-length MAVS from spontaneous aggregation through transmembrane domain-mediated homotypic interaction. Without these shorter isoforms, full-length MAVS is prone to spontaneous aggregation and Nix-mediated mitophagic degradation. In the absence of N-terminally truncated forms, blocking Nix-mediated mitophagy stabilizes full-length MAVS, which aggregates spontaneously and induces the subsequent expression of type I interferon and other proinflammatory cytokines. Our data thus uncover an important mechanism preventing spontaneous aggregation of endogenous MAVS to avoid accidental activation of antiviral innate immune signalling.

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An autoinhibitory mechanism modulates MAVS activity in antiviral innate immune response

Cited by 42 publications

References 43 publications

Ube2D3 and Ube2N are essential for RIG-I-mediated MAVS aggregation in antiviral innate immunity

Ube2D3 and Ube2N are essential for RIG-I-mediated MAVS aggregation in antiviral innate immunity

Filament assemblies in foreign nucleic acid sensors

Multiple truncated isoforms of MAVS prevent its spontaneous aggregation in antiviral innate immune signalling

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