期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 17, 页码 -出版社
MDPI
DOI: 10.3390/ijms22179233
关键词
SARS-CoV-2; COVID19; B; 1; 1; 7; variant of concern; Orf9b; TOM70; mitochondria; Hsp90; interferon
资金
- FoRUM grant from the Medical Faculty of the Ruhr University Bochum [F1014-2021]
This study explores the interaction mechanism between the SARS-CoV-2 viral protein Orf9b and the mitochondrial protein TOM70, revealing that binding of Orf9b to TOM70 inhibits the recruitment of Hsp90 and chaperone-associated proteins. It is demonstrated that the formation of the Orf9b-TOM70 complex is regulated by phosphorylation, and the N-terminal TPR domain of TOM70 serves as a second binding site for Orf9b, indicating a previously unobserved contribution of chaperones in the mitochondrial targeting of the viral protein.
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the causative agent of the COVID19 pandemic. The SARS-CoV-2 genome encodes for a small accessory protein termed Orf9b, which targets the mitochondrial outer membrane protein TOM70 in infected cells. TOM70 is involved in a signaling cascade that ultimately leads to the induction of type I interferons (IFN-I). This cascade depends on the recruitment of Hsp90-bound proteins to the N-terminal domain of TOM70. Binding of Orf9b to TOM70 decreases the expression of IFN-I; however, the underlying mechanism remains elusive. We show that the binding of Orf9b to TOM70 inhibits the recruitment of Hsp90 and chaperone-associated proteins. We characterized the binding site of Orf9b within the C-terminal domain of TOM70 and found that a serine in position 53 of Orf9b and a glutamate in position 477 of TOM70 are crucial for the association of both proteins. A phosphomimetic variant Orf9b(S53E) showed drastically reduced binding to TOM70 and did not inhibit Hsp90 recruitment, suggesting that Orf9b-TOM70 complex formation is regulated by phosphorylation. Eventually, we identified the N-terminal TPR domain of TOM70 as a second binding site for Orf9b, which indicates a so far unobserved contribution of chaperones in the mitochondrial targeting of the viral protein.
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