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

Zhou, Yuzheng1,2; Chen, Zongpeng1; Liu, Sijie1; Liu, Sixu1; Liao, Yujie1; Du, Ashuai1; Dong, Zijun3; Zhang, Yongxing1; Chen, Xuan1; Tao, Siyi1; Wu, Xin4; Razzaq, Aroona; Xu, Gang5; Tan, De-an6; Li, Shanni1; Deng, Youwen4; Peng, Jian7; Dai, Shuyan8; Deng, Xu8; Zhang, Xianwen9; Jiang, Taijiao10; Zhang, Zheng2; Cheng, Gong9,11; Zhao, Jincun2,10,12; Xia, Zanxian1,13,14

2024-06-28

10.1038/s41392-024-01874-5

SIGNAL TRANSDUCTION AND TARGETED THERAPY   影响因子和分区

2095-9907

2059-3635

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 (HSP90 alpha) 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 HSP90 alpha 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 HSP90 alpha in lung epithelial cells from COVID-19 patients, suggesting a potential mechanism by which SARS-CoV-2 may exploit HSP90 alpha to evade the host immunity. Our study identifies the CUL5-TOM70-HSP90 alpha 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.

SCI

英语

其他

National Key Research and Development Program of China[2021YFC2300103] ; National Natural Science Foundation of China["U21A20384","82072293"] ; Natural Science Foundation of Hunan Province,China[2022JJ30692] ; China Postdoctoral Science Foundation[2023M731520]

Biochemistry & Molecular Biology ; Cell Biology

Biochemistry & Molecular Biology ; Cell Biology

WOS:001257131100002

SPRINGERNATURE

Web of Science

1.Cent South Univ, Sch Life Sci, Dept Cell Biol, Changsha 410013, Peoples R China
2.Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Affiliated Hosp 2, Inst Hepatol,Natl Clin Res Ctr Infect Dis,Sch Med, Shenzhen 518112, Peoples R China
3.Hunan Normal Univ, Sch Med, Dept Basic Med, Changsha 410081, Peoples R China
4.Cent South Univ, Xiangya Hosp 3, Dept spine Surg, Changsha 410013, Peoples R China
5.Anhui Med Univ, Sch Basic Med Sci, Hefei 230032, Peoples R China
6.Hunan Normal Univ, Affiliated Hosp 2, 921 Hosp Joint Logist Support Force Peoples Liber, Hunan Key Lab Neurorestoratol, Changsha 410003, Hunan, Peoples R China
7.Cent South Univ, Xiangya Hosp, Dept Geriatr Surg, Changsha 410008, Peoples R China
8.Cent South Univ, Xiangya Sch Pharmaceut Sci, Changsha 410013, Peoples R China
9.Shenzhen Bay Lab, Inst Infect Dis, Shenzhen 518132, Peoples R China
10.Guangzhou Lab, Guangzhou 510005, Peoples R China
11.Tsinghua Univ, Sch Med, Tsinghua Univ Peking Univ Joint Ctr Life Sci, Beijing 100084, Peoples R China
12.Guangzhou Med Univ, Affiliated Hosp 1, Guangzhou Inst Resp Hlth, Natl Clin Res Ctr Resp Dis,State Key Lab Resp Dis, Guangzhou 510120, Peoples R China
13.Cent South Univ, Sch Life Sci, Hunan Key Lab Med Genet, Hunan Key Lab Anim Models Human Dis, Changsha 410008, Peoples R China
14.Cent South Univ, Ctr Med Genet, Sch Life Sci, Changsha 410008, Peoples R China

Zhou, Yuzheng,Chen, Zongpeng,Liu, Sijie,et al. A Cullin 5-based complex serves as an essential modulator of ORF9b stability in SARS-CoV-2 replication[J]. SIGNAL TRANSDUCTION AND TARGETED THERAPY,2024,9(1).

Zhou, Yuzheng.,Chen, Zongpeng.,Liu, Sijie.,Liu, Sixu.,Liao, Yujie.,...&Xia, Zanxian.(2024).A Cullin 5-based complex serves as an essential modulator of ORF9b stability in SARS-CoV-2 replication.SIGNAL TRANSDUCTION AND TARGETED THERAPY,9(1).

Zhou, Yuzheng,et al."A Cullin 5-based complex serves as an essential modulator of ORF9b stability in SARS-CoV-2 replication".SIGNAL TRANSDUCTION AND TARGETED THERAPY 9.1(2024).