A Cullin 5-based complex serves as an essential modulator of ORF9b stability in SARS-CoV-2 replication

Zhou, Yuzheng; Chen, Zongpeng; Liu, Sijie; Liu, Sixu; Liao, Yujie; Du, Ashuai; Dong, Zijun; Zhang, Yongxing; Chen, Xuan; Tao, Siyi; Wu, Xin; Razzaq, Aroona; Xu, Gang; Tan, De-an; Li, Shanni; Deng, Youwen; Peng, Jian; Dai, Shuyan; Deng, Xu; Zhang, Xianwen; Jiang, Taijiao; Zhang, Zheng; Cheng, Gong; Zhao, Jincun; Xia, Zanxian

doi:10.1038/s41392-024-01874-5

Cited by 4 publications

References 74 publications

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Lung‐Targeted Lipid Nanoparticle‐Delivered siUSP33 Attenuates SARS‐CoV‐2 Replication and Virulence by Promoting Envelope Degradation

Zhou,

Liao,

Fan

et al. 2024

Advanced Science

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As a structural protein of SARS‐CoV‐2, the envelope (E) protein not only plays a key role in the formation of viral particles, but also forms ion channels and has pathogenic functions, including triggering cell death and inflammatory responses. The stability of E proteins is controlled by the host ubiquitin‐proteasome system. By screening human deubiquitinases, it is found that ubiquitin‐specific protease 33 (USP33) can enhance the stability of E proteins depending on its deubiquitinase activity, thereby promoting viral replication. In the absence of USP33, E proteins are rapidly degraded, leading to a reduced viral load and inflammation. Using lipid nanoparticle (LNP) encapsulation of siUSP33 by adjusting the lipid components (ionizable cationic lipids), siUSP33 is successfully delivered to mouse lung tissues, rapidly reducing USP33 expression in the lungs and maintaining knockdown for at least 14 days, effectively suppressing viral replication and virulence. This method of delivery allows efficient targeting of the lungs and a response to acute infections without long‐term USP33 deficiency. This research, based on the deubiquitination mechanism of USP33 on the E protein, demonstrates that LNP‐mediated siRNA delivery targeting USP33 plays a role in antiviral and anti‐inflammatory responses, offering a novel strategy for the prevention and treatment of SARS‐CoV‐2.

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Lung‐Targeted Lipid Nanoparticle‐Delivered siUSP33 Attenuates SARS‐CoV‐2 Replication and Virulence by Promoting Envelope Degradation

Zhou,

Liao,

Fan

et al. 2024

Advanced Science

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E3 ubiquitin ligase FBXO22 inhibits SARS‐CoV‐2 replication via promoting proteasome‐dependent degradation of NSP5

Zhou,

Feng,

Yang

et al. 2024

Journal of Medical Virology

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The ubiquitin‐proteasome system is frequently employed to degrade viral proteins, thereby inhibiting viral replication and pathogenicity. Through an analysis of the degradation kinetics of all the SARS‐CoV‐2 proteins, our study revealed rapid degradation of several proteins, particularly NSP5. Additionally, we identified FBXO22, an E3 ubiquitin ligase, as the primary regulator of NSP5 ubiquitination. Moreover, we validated the interaction between FBXO22 and NSP5, demonstrating that FBXO22‐mediated ubiquitination of NSP5 facilitated its recognition by the proteasome, leading to subsequent degradation. Specifically, FBXO22 catalyzed the formation of K48‐linked polyubiquitin chains on NSP5 at lysine residues 5 and 90. Knockdown of FBXO22 resulted in decreased NSP5 ubiquitination levels, increased stability, and enhanced ability to evade the host innate immune response. Notably, the protein level of FBXO22 were negatively correlated with SARS‐CoV‐2 load, highlighting its importance in inhibiting viral replication. This study elucidates the molecular mechanism by which FBXO22 mediates the degradation of NSP5 and underscores its critical role in limiting viral replication. The identification of FBXO22 as a regulator of NSP5 stability provides new insights and potential avenues for targeting NSP5 in antiviral strategies.

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Identification and Targeting of Regulators of SARS-CoV-2-Host Interactions in the Airway Epithelium

Dirvin,

Noh,

Tomassoni

et al. 2024

Preprint

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Although the impact of SARS-CoV-2 in the lung has been extensively studied, the molecular regulators and targets of the host-cell programs hijacked by the virus in distinct human airway epithelial cell populations remain poorly understood. This is in part ascribed to the use of non- primary cell systems, overreliance on single-cell gene expression profiling that not ultimately reflect protein activity and bias toward the downstream effects rather than their mechanistic determinants. Here we address these issues by network-based analysis of single cell transcriptomic profiles of pathophysiologically relevant human adult basal, ciliated and secretory cells to identify master regulator (MR) protein modules controlling their SARS-CoV-2-mediated reprogramming. This uncovered chromatin remodeling, endosomal sorting, ubiquitin pathway as well as proviral factors identified by CRISPR analyses as components of the host response collectively or selectively activated in these cells. Large-scale perturbation assays, using a clinically-relevant drug library, identified 11 drugs able to invert the entire MR signature activated by SARS-CoV-2 in these cell types. Leveraging MR analysis and perturbational profiles of human primary cells, represents a novel mechanism-based approach and resource that can be directly generalized to interrogate signatures of other airway conditions for drug prioritization.

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A Cullin 5-based complex serves as an essential modulator of ORF9b stability in SARS-CoV-2 replication

Cited by 4 publications

References 74 publications

Lung‐Targeted Lipid Nanoparticle‐Delivered siUSP33 Attenuates SARS‐CoV‐2 Replication and Virulence by Promoting Envelope Degradation

Lung‐Targeted Lipid Nanoparticle‐Delivered siUSP33 Attenuates SARS‐CoV‐2 Replication and Virulence by Promoting Envelope Degradation

E3 ubiquitin ligase FBXO22 inhibits SARS‐CoV‐2 replication via promoting proteasome‐dependent degradation of NSP5

Identification and Targeting of Regulators of SARS-CoV-2-Host Interactions in the Airway Epithelium

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