SARS-CoV-2 Orf9b suppresses type I interferon responses by targeting TOM70

Jiang, He; Zhang, Hai nan; Meng, Qiong; Xie, Jia Zheng; Li, Yang; Chen, Hong; Zheng, Yun; Wang, Xue ning; Qi, Huan; Zhang, Jing; Wang, Pei‐Hui; Han, Ze‐Guang; Tao, Sheng Ce

doi:10.1038/s41423-020-0514-8

Cited by 313 publications

(310 citation statements)

References 18 publications

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“…During the preparation of this manuscript, another recently showed that SARS-CoV-2 ORF9b suppresses type I interferon responses by targeting TOM70. 39 Although the molecular mechanism of how Orf9b inhibits type I IFN responses through interacting with TOM70 is not investigated, it is proposed that ORF9b may compete with HSP90 for binding to TOM70 or may induce the production of lactic acid, which has been proven to inhibit IFN-I responses. 39 Consistent with the above findings, we demonstrated that SARS-CoV-2 ORF9b inhibits the production of type I IFN induced by SeV infection, poly (I:C) stimulation, and the activation of RIG-I/MDA-5-MAVS, TLR3-TRIF, and cGAS-STING signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 ORF9b Antagonizes Type I and III Interferons by Targeting Multiple Components of RIG-I/MDA-5-MAVS, TLR3-TRIF, and cGAS-STING Signaling Pathways

Han

Zhuang

Zheng

et al. 2020

Preprint

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Severe acute respiratory syndrome corona-virus 2 (SARS-CoV-2), the etiologic agent of the coronavirus disease 2019 (COVID-19), has a catastrophic effect on human health and society. Clinical findings indicated that the suppression of innate antiviral immunity, especially the type I and III interferon (IFN) production, contributes to the pathogenesis of COVID-19. However, how SARS-CoV-2 evades antiviral immunity still needs further investigations. Here, we reported that the open reading frame 9b (ORF9b) protein encoded by the SARS-CoV-2 genome inhibits the activation of type I and III IFN response by targeting multiple molecules of innate antiviral signaling pathways. SARS-CoV-2 ORF9b impaired the induction of type I and III IFNs by Sendai virus or the dsRNA mimic poly (I:C). SARS-CoV-2 ORF9b inhibits the activation of type I and III IFNs induced by the components of cytosolic dsRNA-sensing pathways of RIG-I/MDA5-MAVS signaling, including RIG-I, MDA-5, MAVS, TBK1, and IKKε rather than IRF3-5D, the active form of IRF3. SARS-CoV-2 ORF9b also suppressed the induction of type I and III IFNs by TRIF and STING, the adaptor protein of endosome RNA-sensing pathway of TLR3-TRIF signaling and the adaptor protein of cytosolic DNA-sensing pathway of cGAS-STING signaling, respectively. Mechanistically, SARS-CoV-2 ORF9b protein interacts with RIG-I, MDA-5, MAVS, TRIF, STING, TBK1, and prevents TBK1 phosphorylation, thus impeding the phosphorylation and nuclear trans-localization of IRF3 activation. Overexpression of SARS-CoV-2 ORF9b facilitates the replication of the vesicular stomatitis virus. Therefore, SARS-CoV-2 ORF9b negatively regulates antiviral immunity, thus, facilitate virus replication. This study contributes to our understanding of the molecular mechanism of how SARS-CoV-2 impaired antiviral immunity and providing an essential clue to the pathogenesis of COVID-19.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 ORF9b Antagonizes Type I and III Interferons by Targeting Multiple Components of RIG-I/MDA-5-MAVS, TLR3-TRIF, and cGAS-STING Signaling Pathways

Han

Zhuang

Zheng

et al. 2020

Preprint

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“…2b), ORF9B yielded a unique interaction profile enriched for mitochondrial proteins (GO CC p adj 1.29e -28 for the C-term and 3.10e -157 for N-term interactomes, respectively). Tagged at either terminus, ORF9B recovered a number of outer mitochondrial membrane proteins, including TOMM70, a mitochondrial import receptor subunit shown to associate with ORF9B in three other studies 6,7,32 , and whose binding can be recapitulated in vitro by purified proteins 32 . ORF9B also recovers many peptides for MAVS, a protein required for innate immune defense against viruses (reviewed in 33 ) that we previously studied in the context of a BioID map of mitochondrial organization 34 .…”

Section: Nsp7 and Nsp8mentioning

confidence: 98%

A SARS-CoV-2 – host proximity interactome

Samavarchi-Tehrani

Abdouni

Knight

et al. 2020

Preprint

131

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Viral replication is dependent on interactions between viral polypeptides and host proteins. Identifying virus-host protein interactions can thus uncover unique opportunities for interfering with the virus life cycle via novel drug compounds or drug repurposing. Importantly, many viral-host protein interactions take place at intracellular membranes and poorly soluble organelles, which are difficult to profile using classical biochemical purification approaches. Applying proximity-dependent biotinylation (BioID) with the fast-acting miniTurbo enzyme to 27 SARS-CoV-2 proteins in a lung adenocarcinoma cell line (A549), we detected 7810 proximity interactions (7382 of which are new for SARS-CoV-2) with 2242 host proteins (results available at covid19interactome.org). These results complement and dramatically expand upon recent affinity purification-based studies identifying stable host-virus protein complexes, and offer an unparalleled view of membrane-associated processes critical for viral production. Host cell organellar markers were also subjected to BioID in parallel, allowing us to propose modes of action for several viral proteins in the context of host proteome remodelling. In summary, our dataset identifies numerous high confidence proximity partners for SARS-CoV-2 viral proteins, and describes potential mechanisms for their effects on specific host cell functions.

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“…The Kelhr laboratory also reports SARS-CoV-1 ORF9b property of triggering autophagy in an ATG5-dependent manner when highly expressed 166 . ORF9b is located at the outer mitochondrial membrane probably via its interaction with TOMM70A 167 . This recent study suggests that the ORF9b-TOMM70A interaction is essential for the type I IFN signaling inhibition role of ORF9b.…”

Section: Orf9b Interacts With Major Innate Immune Pathway Factors (Mamentioning

confidence: 99%

Global BioID-based SARS-CoV-2 proteins proximal interactome unveils novel ties between viral polypeptides and host factors involved in multiple COVID19-associated mechanisms

Laurent

Sofianatos

Komarova

et al. 2020

Preprint

128

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The worldwide SARS-CoV-2 outbreak poses a serious challenge to human societies and economies. SARS-CoV-2 proteins orchestrate complex pathogenic mechanisms that underlie COVID-19 disease. Thus, understanding how viral polypeptides rewire host protein networks enables better-founded therapeutic research. In complement to existing proteomic studies, in this study we define the first proximal interaction network of SARS-CoV-2 proteins, at the whole proteome level in human cells. Applying a proximity-dependent biotinylation (BioID)-based approach greatly expanded the current knowledge by detecting interactions within poorly soluble compartments, transient, and/or of weak affinity in living cells. Our BioID study was complemented by a stringent filtering and uncovered 2,128 unique cellular targets (1,717 not previously associated with SARS-CoV-1 or 2 proteins) connected to the N- and C-ter BioID-tagged 28 SARS-CoV-2 proteins by a total of 5,415 (5,236 new) proximal interactions. In order to facilitate data exploitation, an innovative interactive 3D web interface was developed to allow customized analysis and exploration of the landscape of interactions (accessible at http://www.sars-cov-2-interactome.org/). Interestingly, 342 membrane proteins including interferon and interleukin pathways factors, were associated with specific viral proteins. We uncovered ORF7a and ORF7b protein proximal partners that could be related to anosmia and ageusia symptoms. Moreover, comparing proximal interactomes in basal and infection-mimicking conditions (poly(I:C) treatment) allowed us to detect novel links with major antiviral response pathway components, such as ORF9b with MAVS and ISG20; N with PKR and TARB2; NSP2 with RIG-I and STAT1; NSP16 with PARP9-DTX3L. Altogether, our study provides an unprecedented comprehensive resource for understanding how SARS-CoV-2 proteins orchestrate host proteome remodeling and innate immune response evasion, which can inform development of targeted therapeutic strategies.

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SARS-CoV-2 Orf9b suppresses type I interferon responses by targeting TOM70

Cited by 313 publications

References 18 publications

SARS-CoV-2 ORF9b Antagonizes Type I and III Interferons by Targeting Multiple Components of RIG-I/MDA-5-MAVS, TLR3-TRIF, and cGAS-STING Signaling Pathways

SARS-CoV-2 ORF9b Antagonizes Type I and III Interferons by Targeting Multiple Components of RIG-I/MDA-5-MAVS, TLR3-TRIF, and cGAS-STING Signaling Pathways

A SARS-CoV-2 – host proximity interactome

Global BioID-based SARS-CoV-2 proteins proximal interactome unveils novel ties between viral polypeptides and host factors involved in multiple COVID19-associated mechanisms

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