The mitochondrial ubiquitin ligase MARCH5 resolves MAVS aggregates during antiviral signalling

Yoo, Young-Suk; Park, Yong-Yea; Kim, Jae-Hoon; Cho, Hyeseon; Kim, Songhee; Lee, Ho-Soo; Kim, Tae‐Hwan; Kim, You Sun; Lee, Youngsoo; Kim, Chul-Joong; Jung, Jae U.; Lee, Jong-Soo; Cho, Hyeseong

doi:10.1038/ncomms8910

Cited by 132 publications

(135 citation statements)

References 56 publications

(85 reference statements)

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“…For example, both Smurf1 and Smurf2 E3 ubiquitin ligases interact with MAVS and target MAVS for K48-linked ubiquitination (42,43). The mitochondrial ubiquitin ligase MARCH5 induces proteasome-mediated degradation of MAVS at Lys7 and Lys500 and modulates MAVS-mediated antiviral signaling (44). Until now, only the HECT domain E3 ligase AIP4 has been identified to be involved in virus-mediated MAVS degradation.…”

Section: Discussionmentioning

confidence: 99%

Newcastle Disease Virus V Protein Degrades Mitochondrial Antiviral Signaling Protein To Inhibit Host Type I Interferon Production via E3 Ubiquitin Ligase RNF5

Sun

Zheng

et al. 2019

J Virol

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Paramyxovirus establishes an intimate and complex interaction with the host cell to counteract the antiviral responses elicited by the cell. Of the various pattern recognition receptors in the host, the cytosolic RNA helicases interact with viral RNA to activate the mitochondrial antiviral signaling protein (MAVS) and subsequent cellular interferon (IFN) response. On the other hand, viruses explore multiple strategies to resist host immunity. In this study, we found that Newcastle disease virus (NDV) infection induced MAVS degradation. Further analysis showed that NDV V protein degraded MAVS through the ubiquitin-proteasome pathway to inhibit IFN-␤ production. Moreover, NDV V protein led to proteasomal degradation of MAVS through Lys362 and Lys461 ubiquitin to prevent IFN production. Further studies showed that NDV V protein recruited E3 ubiquitin ligase RNF5 to polyubiquitinate and degrade MAVS. Compared with levels for wild-type NDV infection, V-deficient NDV induced attenuated MAVS degradation and enhanced IFN-␤ production at the late stage of infection. Several other paramyxovirus V proteins showed activities of degrading MAVS and blocking IFN production similar to those of NDV V protein. The present study revealed a novel role of NDV V protein in targeting MAVS to inhibit cellular IFN production, which reinforces the fact that the virus orchestrates the cellular antiviral response to its own benefit. IMPORTANCE Host anti-RNA virus innate immunity relies mainly on the recognition by retinoic acid-inducible gene I and melanoma differentiation-associated protein 5 and subsequently initiates downstream signaling through interaction with MAVS. On the other hand, viruses have developed various strategies to counteract MAVSmediated signaling. The mechanism for paramyxoviruses regulating MAVS to benefit their infection remains unknown. In this article, we demonstrate that the V proteins of NDV and several other paramyxoviruses target MAVS for ubiquitin-mediated degradation through E3 ubiquitin ligase RING-finger protein 5 (RNF5). MAVS degradation leads to the inhibition of the downstream IFN-␤ pathway and therefore benefits virus proliferation. Our study reveals a novel mechanism of NDV evading host innate immunity and provides insight into the therapeutic strategies for the control of paramyxovirus infection.

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Section: Discussionmentioning

confidence: 99%

Newcastle Disease Virus V Protein Degrades Mitochondrial Antiviral Signaling Protein To Inhibit Host Type I Interferon Production via E3 Ubiquitin Ligase RNF5

Sun

Zheng

et al. 2019

J Virol

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“…In keeping with this, the level of MAVS was shown to decrease shortly after its activation through several distinct mechanisms. This includes Atg5-mediated autophagy of mitochondria (mitophagy) 54 , ubiquitin-mediated proteosomal degradation of MAVS (through the actions of E3 ligases, Smurf2 55 , March5 56 and pVHL 57 ). Other more complex regulatory mechanisms involving miniMAVS 58 , Trim25 59 and IRTKS 60 were also proposed.…”

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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“…It has been reported that the structure of a protein is associated with its function (50). Of note, Piasy binds to Rbp2 via its 101–218 aa (Fig.…”

Section: Discussionmentioning

confidence: 99%

Chromatin remodeling: demethylating H3K4me3 of type I IFNs gene by Rbp2 through interacting with Piasy for transcriptional attenuation

Chen

Zuo

et al. 2018

FASEB j.

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Type I IFNs (IFNIs) are involved in the course of antiviral and antimicrobial activities; however, robust inductions of these can lead to host immunopathology. We have reported that the Pias (protein inhibitor of activated signal transducer and activator of transcription) family member, Piasy, possesses the ability to suppress IFNI transcriptions in mouse embryonic fibroblasts (MEFs), yet the specific molecular mechanism by which it acts remains elusive. Here, we identify that the H3K4me3 levels, one activation mark of genes, in MEFs that were stimulated by poly(I:C) were impaired by Piasy in the IFN-β gene. Piasy bound to the promoter region of the IFN-β gene in MEFs. Meanwhile, retinoblastoma binding protein 2 (Rbp2) was proven to be the only known and novel H3K4me3 demethylase that interacted with Piasy. Overexpression of Rbp2, but not its enzymatically inactive mutant Rbp2, retarded the transcription activities of IFNI, whereas small interfering RNA-mediated or short hairpin RNA-mediated knockdown of Rbp2 enhanced IFNI promoter responses. Above all, coexpression of Piasy and Rbp2 led to statistically less IFNI induction than overexpression of either Piasy or Rbp2 alone. Mechanistically, Piasy bound to the Jmjc domain (451-503 aa) of Rbp2 via its PINIT domain (101-218 aa), which is consistent with the domain required for their attenuation of transcription and H3K4me3 levels of IFNI genes. Our study demonstrates that Piasy may prevent exaggerated transcription of IFNI by Rbp2-mediated demethylation of H3K4me3 of IFNI, avoiding excessive immune responses.-Yu, X., Chen, H., Zuo, C., Jin, X., Yin, Y., Wang, H., Jin, M., Ozato, K., Xu, S. Chromatin remodeling: demethylating H3K4me3 of type I IFNs gene by Rbp2 through interacting with Piasy for transcriptional attenuation.

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The mitochondrial ubiquitin ligase MARCH5 resolves MAVS aggregates during antiviral signalling

Cited by 132 publications

References 56 publications

Newcastle Disease Virus V Protein Degrades Mitochondrial Antiviral Signaling Protein To Inhibit Host Type I Interferon Production via E3 Ubiquitin Ligase RNF5

Newcastle Disease Virus V Protein Degrades Mitochondrial Antiviral Signaling Protein To Inhibit Host Type I Interferon Production via E3 Ubiquitin Ligase RNF5

Filament assemblies in foreign nucleic acid sensors

Chromatin remodeling: demethylating H3K4me3 of type I IFNs gene by Rbp2 through interacting with Piasy for transcriptional attenuation

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