ArticleSignal transduction and targeted therapy2024
A Cullin 5-based complex serves as an essential modulator of ORF9b stability in SARS-CoV-2 replication.
Article in Signal transduction and targeted therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Sarbecoviruses Suppress Innate Immunity by Recruiting PPM1A to Modulate STAT2 and ORF9b Phosphorylation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Article
- CUL5 E3 ubiquitin ligase regulates the evasion of bladder cancer cells to CD8+ T cell-mediated killing by inhibiting autophagy.PLoS biology · 2026Article
- The roles of post-translational modifications in the pathogenesis of RNA viruses: allies or adversaries?Frontiers in microbiology · 2026Review
- Cul5: immune cell function and therapeutic potential.Frontiers in immunology · 2026Review
- Rewriting the viral script: post-translational modifications orchestrating SARS-CoV-2 pathogenesis and immune evasion.Frontiers in microbiology · 2026Review
- Ubiquitin D Promotes Lung Metastasis by Stabilizing MMP3 in Triple-Negative Breast Cancer.Research (Washington, D.C.) · 2026Article
- A comprehensive PDCoV-host proteome interaction map reveals potential antiviral targets.PLoS pathogens · 2025Article
- NSP7 Molecular Degrader Attenuates Coronaviral Infection Through the β-TrCP1/FBXO5 Axis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Identification and targeting of regulators of SARS-CoV-2-host interactions in the airway epithelium.Science advances · 2025Article
- Pathogen-induced mitochondrial dysfunction: mechanistic insights, immune crosstalk, and therapeutic opportunities.Frontiers in cellular and infection microbiology · 2025Review
- Lung-Targeted Lipid Nanoparticle-Delivered siUSP33 Attenuates SARS-CoV-2 Replication and Virulence by Promoting Envelope Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
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Authors and funding
25 authors.
Funding
Abstract
The ORF9b protein, derived from the nucleocapsid's open-reading frame in both SARS-CoV and SARS-CoV-2, serves as an accessory protein crucial for viral immune evasion by inhibiting the innate immune response. Despite its significance, the precise regulatory mechanisms underlying its function remain elusive. In the present study, we unveil that the ORF9b protein of SARS-CoV-2, including emerging mutant strains like Delta and Omicron, can undergo ubiquitination at the K67 site and subsequent degradation via the proteasome pathway, despite certain mutations present among these strains. Moreover, our investigation further uncovers the pivotal role of the translocase of the outer mitochondrial membrane 70 (TOM70) as a substrate receptor, bridging ORF9b with heat shock protein 90 alpha (HSP90α) and Cullin 5 (CUL5) to form a complex. Within this complex, CUL5 triggers the ubiquitination and degradation of ORF9b, acting as a host antiviral factor, while HSP90α functions to stabilize it. Notably, treatment with HSP90 inhibitors such as GA or 17-AAG accelerates the degradation of ORF9b, leading to a pronounced inhibition of SARS-CoV-2 replication. Single-cell sequencing data revealed an up-regulation of HSP90α in lung epithelial cells from COVID-19 patients, suggesting a potential mechanism by which SARS-CoV-2 may exploit HSP90α to evade the host immunity. Our study identifies the CUL5-TOM70-HSP90α complex as a critical regulator of ORF9b protein stability, shedding light on the intricate host-virus immune response dynamics and offering promising avenues for drug development against SARS-CoV-2 in clinical settings.
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