The ORF3a protein of SARS-CoV-2 induces apoptosis in cells

Ren, Yujie; Shu, Ting; Wu, Di; Mu, Jian; Wang, Chong; Huang, Mingbin; Han, Yu; Zhang, Xue Yi; Zhou, Wenchen; Qiu, Yang; Zhou, Xi

doi:10.1038/s41423-020-0485-9

Cited by 439 publications

(467 citation statements)

References 9 publications

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“…Of note, we identified 12 factors involved in virus entry mechanisms. We detected ORF3a is a key accessory protein showing a pro-apoptotic activity 76 . 83 .…”

Section: Nsp14 Associates With Rna Decapping and Deadenylation Host Fmentioning

confidence: 88%

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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“…Of note, we identified 12 factors involved in virus entry mechanisms. We detected ORF3a is a key accessory protein showing a pro-apoptotic activity 76 . 83 .…”

Section: Nsp14 Associates With Rna Decapping and Deadenylation Host Fmentioning

confidence: 88%

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

View full text Add to dashboard Cite

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“…Spatiotemporally, mutation Q57H locates at the intramolecular interface and in touch with the membrane, which indicates the special functionality changes that Q57H can induce., and Figure 8 (b) is the visualization of ORF3a, which is generated by an The ORF3a gene of SARS-CoV-2 encodes 275 amino acids with TNF receptor-associated factors (TRAFs), ion channel, and caveolin binding domain. Previous studies have shown that SARS-CoV ORF3a contains a cysteine-rich motif, a tyrosine-based sorting motif, and a diacidic EXD motif, which are the critical domains that participate in the apoptosis and activate the innate immune signaling receptor NLRP3 (NOD-, LRR-, and pyrin domain-containing 3) inflammasome [16,30]. ORF3a of SARS-CoV-2 shares 71.53% similarity Figure 6: Illustration of S-protein and ACE2 interaction.…”

Section: Mutation On the Orf3a Proteinmentioning

confidence: 99%

Characterizing SARS-CoV-2 mutations in the United States

Wang

Chen

Gao

et al. 2020

Preprint

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been mutating since it was first sequenced in early January 2020. The genetic variants have developed into a few distinct clusters with different properties. Since the United States (US) has the highest number of viral infected patients globally, it is essential to understand the US SARS-CoV-2. Using genotyping, sequence-alignment, time-evolution, k-means clustering, protein-folding stability, algebraic topology, and network theory, we reveal that the US SARS-CoV-2 has four substrains and five top US SARS-CoV-2 mutations were first detected in China (2 cases), Singapore (2 cases), and the United Kingdom (1 case). The next three top US SARS-CoV-2 mutations were first detected in the US. These eight top mutations belong to two disconnected groups. The first group consisting of 5 concurrent mutations is prevailing, while the other group with three concurrent mutations gradually fades out. We identify that one of the top mutations, 27964C>T-(S24L) on ORF8, has an unusually strong gender dependence. Based on the analysis of all mutations on the spike protein, we further uncover that three of four US SASR-CoV-2 substrains become more infectious. Our study calls for effective viral control and containing strategies in the US.

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“…In the lung, SARS-CoV-2 infects ciliated cells in the airway, alveolar type 2 pneumocytes and epithelial progenitors among others [7][8][9] . SARS-CoV-2 and other coronaviruses are cytopathic [10][11][12][13][14] . The death of infected cells is also a trigger of immune activation.…”

Section: Introductionmentioning

confidence: 99%

Syncytia formation by SARS-CoV-2 infected cells

Buchrieser

Dufloo

Hubert

et al. 2020

Preprint

113

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Severe cases of COVID-19 are associated with extensive lung damage and the presence of infected multinucleated syncytial pneumocytes. The viral and cellular mechanisms regulating the formation of these syncytia are not well understood. Here, we show that SARS-CoV-2 infected cells express the viral Spike protein (S) at their surface and fuse with ACE2-positive neighbouring cells. Expression of S without any other viral proteins triggers syncytia formation. Type-I interferon (IFN)-induced transmembrane proteins (IFITMs), a family of restriction factors that block the entry of many viruses, inhibit S-mediated fusion, with IFITM1 being more active than IFITM2 and IFITM3. On the contrary, the TMPRSS2 serine protease, which is known to enhance infectivity of cell-free virions, processes both S and ACE2 and increases syncytia formation by accelerating the fusion process. TMPRSS2 thwarts the antiviral effect of IFITMs. Our results show that the pathological effects of SARS-CoV-2 are modulated by cellular proteins that either inhibit or facilitate syncytia formation.

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The ORF3a protein of SARS-CoV-2 induces apoptosis in cells

Cited by 439 publications

References 9 publications

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

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

Characterizing SARS-CoV-2 mutations in the United States

Syncytia formation by SARS-CoV-2 infected cells

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