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

Zhou, Yuzheng1; Feng, Wei1; Yang, Chuwei1; Wei, Xiafei1; Fan, Lujie1; Wu, Yezi1; Gao, Xiang1; Shen, Xiaotong1; Zhang, Zheng1,2; Zhao, Juanjuan1

2024-09-01

10.1002/jmv.29891

JOURNAL OF MEDICAL VIROLOGY   影响因子和分区

0146-6615

1096-9071

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.

degradation NSP5 SARS-CoV-2 ubiquitination viral replication

SCI

英语

第一 ; 通讯

Chinese Academy of Medical Sciences Clinical and Translational Medicine Research Project[2022-I2M-CT-B-113] ; Major Project of Guangzhou National Laboratory[GZNL2024A01014] ; National Science Fund for Distinguished Young Scholars[82025022] ; National Natural Science Foundation of China[92369109] ; China Postdoctoral Science Foundation[2023M731520] ; Guangdong Science and Technology Plan Project, Construction of high-level biosafety laboratories[2021B1212030010] ; Guangdong Basic and Applied Basic Research Foundation["2024A1515012490","2023A1515111136","2023A1515110033"] ; Shenzhen Science and Technology Program["JCYJ20220818103017036","RCBS20231211090709013"] ; null[2021YFA0910900]

Virology

Virology

WOS:001321738800032

WILEY

Web of Science

1.Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Affiliated Hosp 2, Inst Hepatol,Sch Med,Natl Clin Res Ctr Infect Dis, Shenzhen 518112, Peoples R China
2.Chinese Acad Med Sci, Shenzhen Res Ctr Communicable Dis Diag & Treatment, Shenzhen, Peoples R China

Zhou, Yuzheng,Feng, Wei,Yang, Chuwei,et al. E3 ubiquitin ligase FBXO22 inhibits SARS-CoV-2 replication via promoting proteasome-dependent degradation of NSP5[J]. JOURNAL OF MEDICAL VIROLOGY,2024,96(9).

Zhou, Yuzheng.,Feng, Wei.,Yang, Chuwei.,Wei, Xiafei.,Fan, Lujie.,...&Zhao, Juanjuan.(2024).E3 ubiquitin ligase FBXO22 inhibits SARS-CoV-2 replication via promoting proteasome-dependent degradation of NSP5.JOURNAL OF MEDICAL VIROLOGY,96(9).

Zhou, Yuzheng,et al."E3 ubiquitin ligase FBXO22 inhibits SARS-CoV-2 replication via promoting proteasome-dependent degradation of NSP5".JOURNAL OF MEDICAL VIROLOGY 96.9(2024).