Phosphorylation of SARS-CoV-2 Orf9b Regulates Its Targeting to Two Binding Sites in TOM70 and Recruitment of Hsp90

Brandherm, Lukas; Kobaš, Antonio Mario; Klöhn, Mara; Brüggemann, Yannick; Pfaender, Stephanie; Rassow, Joachim; Kreimendahl, Sebastian

doi:10.3390/ijms22179233

Cited by 27 publications

(31 citation statements)

References 49 publications

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“…This cascade depends on the recruitment of Hsp90-bound proteins to the N-terminal domain of TOM70, thus recruiting TBK1/IRF3 to mitochondria, and disruption of this interaction impairs the activation of TBK1 and IRF3, which are critical steps to the mitochondrial antiviral system and induction of type I interferons (IFN–I) [ 10 , 29 ]. Therefore, our results and analyses provide several lines of evidence that support the findings that inhibition of Hsp90 binding to TOM70 by ORF9b is the reason for the reduced IFN-I and overall host immune evasion of SAR-CoV-2 [ 30 ].…”

Section: Resultssupporting

confidence: 83%

Binding of SARS-CoV-2 protein ORF9b to mitochondrial translocase TOM70 prevents its interaction with chaperone HSP90

2022

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Section: Resultssupporting

confidence: 83%

Binding of SARS-CoV-2 protein ORF9b to mitochondrial translocase TOM70 prevents its interaction with chaperone HSP90

2022

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“…The protein 8b encoded by an internal ORF within the N gene via a ribosomal leaky scanning mechanism ( 11 ), which is similar to protein internal (I) in MHV, protein 9b in SARS-CoV, protein N2 in HKU1, and protein 9b in SARS-CoV-2 ( 17 ) SARS-CoV 9b can induce caspase-dependent apoptosis ( 18 ), or suppresses innate immunity by targeting mitochondria and the MAVS/TRAF3/TRAF6 signalosome ( 19 ). SARS-CoV-2 9b can inhibit IFN-I responses by targeting TOM70 ( 20 , 21 ), or suppress IFN-I/III production induced by RIG-I/MDA5-MAVS signaling ( 22 ). MERS-CoV protein 8b can antagonize nuclear factor kappa B (NF-κB) activation or IFN-β promoter activation by luciferase reporter assay ( 23 , 24 ).…”

Section: Introductionmentioning

confidence: 99%

The N-Terminal Region of Middle East Respiratory Syndrome Coronavirus Accessory Protein 8b Is Essential for Enhanced Virulence of an Attenuated Murine Coronavirus

Jin

Kuang

et al. 2022

J Virol

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Middle East respiratory syndrome coronavirus (MERS-CoV) is a beta coronavirus that emerged in 2012, causing severe pneumonia and renal failure. MERS-CoV encodes five accessory proteins. Some of them have been shown to interfere with host antiviral immune response. However, the roles of protein 8b in innate immunity and viral virulence was rarely studied. Here, we introduced individual MERS-CoV accessory protein genes into the genome of an attenuated murine coronavirus (Mouse hepatitis virus, MHV), respectively and found accessory protein 8b could enhance viral replication in vivo and in vitro , and increase the lethality of infected mice. RNA-seq analysis revealed that protein 8b could significantly inhibit type I interferon production (IFN-I) and innate immune response in mice infected with MHV expressing protein 8b. We also found that MERS-CoV protein 8b could initiate from multiple internal methionine sites and at least three protein variants were identified. Residues 1-23 of protein 8b was demonstrated to be responsible for increased virulence in vivo . In addition, the inhibitory effect on IFN-I of protein 8b might not contribute to its virulence enhancement as aa1-23 deletion did not affect IFN-I production in vitro and in vivo . Next, we also found that protein 8b was localized to the endoplasmic reticulum (ER)/Golgi membrane in infected cells, which was disrupted by C-terminal region aa 88-112 deletion. This study will provide new insight into the pathogenesis of MERS-CoV infection. IMPORTANCE Multiple coronaviruses (CoV) cause severe respiratory infections and become global public health threats such as SARS-CoV, MERS-CoV, and SARS-CoV-2. Each coronavirus contains different numbers of accessory proteins which show high variability among different CoVs. Accessory proteins are demonstrated to play essential roles in pathogenesis of CoVs. MERS-CoV contains 5 accessory proteins (protein 3, 4a, 4b, 5, 8b), and deletion of all four accessory proteins (protein 3, 4a, 4b, 5), significantly affects MERS-CoV replication and pathogenesis. However, whether ORF8b also regulates MERS-CoV infection is unknown. Here, we constructed mouse hepatitis virus (MHV) recombinant virus expressing MERS-CoV protein 8b and demonstrated protein 8b could significantly enhance the virulence of MHV, which is mediated by N-terminal domain of protein 8b. This study will shed light on the understanding of pathogenesis of MERS-CoV infection.

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“…Blocks the signaling pathways from TNF receptors by acting on TRAF3 and TRAF6 (TNF receptor-associated factor 3 and 6), disrupts IFN-I synthesis, and induces ATG5-mediated autophagy in host cells [189]. Blocks TOM70, a key adapter that transmits an antiviral signal from the mitochondrial RLR/MAVS pathway to TBK1/IRF3 to induce an IFN response [203,204]. Interacts with RIG-I, MDA-5, MAVS, STING, and TBK1, prevents phosphorylation and nuclear translocation of IRF3, NF-κB activation, and inhibits TRIF (TLR adapter) [205,206].…”

Section: Orf9bmentioning

confidence: 99%

SARS-CoV-2-Specific Immune Response and the Pathogenesis of COVID-19

Gusev

Sarapultsev

Соломатина

et al. 2022

IJMS

181

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The review aims to consolidate research findings on the molecular mechanisms and virulence and pathogenicity characteristics of coronavirus disease (COVID-19) causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and their relevance to four typical stages in the development of acute viral infection. These four stages are invasion; primary blockade of antiviral innate immunity; engagement of the virus’s protection mechanisms against the factors of adaptive immunity; and acute, long-term complications of COVID-19. The invasion stage entails the recognition of the spike protein (S) of SARS-CoV-2 target cell receptors, namely, the main receptor (angiotensin-converting enzyme 2, ACE2), its coreceptors, and potential alternative receptors. The presence of a diverse repertoire of receptors allows SARS-CoV-2 to infect various types of cells, including those not expressing ACE2. During the second stage, the majority of the polyfunctional structural, non-structural, and extra proteins SARS-CoV-2 synthesizes in infected cells are involved in the primary blockage of antiviral innate immunity. A high degree of redundancy and systemic action characterizing these pathogenic factors allows SARS-CoV-2 to overcome antiviral mechanisms at the initial stages of invasion. The third stage includes passive and active protection of the virus from factors of adaptive immunity, overcoming of the barrier function at the focus of inflammation, and generalization of SARS-CoV-2 in the body. The fourth stage is associated with the deployment of variants of acute and long-term complications of COVID-19. SARS-CoV-2’s ability to induce autoimmune and autoinflammatory pathways of tissue invasion and development of both immunosuppressive and hyperergic mechanisms of systemic inflammation is critical at this stage of infection.

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Phosphorylation of SARS-CoV-2 Orf9b Regulates Its Targeting to Two Binding Sites in TOM70 and Recruitment of Hsp90

Cited by 27 publications

References 49 publications

Binding of SARS-CoV-2 protein ORF9b to mitochondrial translocase TOM70 prevents its interaction with chaperone HSP90

Binding of SARS-CoV-2 protein ORF9b to mitochondrial translocase TOM70 prevents its interaction with chaperone HSP90

The N-Terminal Region of Middle East Respiratory Syndrome Coronavirus Accessory Protein 8b Is Essential for Enhanced Virulence of an Attenuated Murine Coronavirus

SARS-CoV-2-Specific Immune Response and the Pathogenesis of COVID-19

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