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SARS-CoV-2 ORF10 impairs cilia by enhancing CUL2(ZYG11B) activity

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal pathogen of the ongoing global pandemic of coronavirus disease 2019 (COVID-19). Loss of smell and taste are symptoms of COVID-19, and may be related to cilia dysfunction. Here, we found that the SARS-CoV-2 ORF10 increases the...

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Detalles Bibliográficos
Autores principales: Wang, Liying, Liu, Chao, Yang, Bo, Zhang, Haotian, Jiao, Jian, Zhang, Ruidan, Liu, Shujun, Xiao, Sai, Chen, Yinghong, Liu, Bo, Ma, Yanjie, Duan, Xuefeng, Guo, Yueshuai, Guo, Mengmeng, Wu, Bingbing, Wang, Xiangdong, Huang, Xingxu, Yang, Haitao, Gui, Yaoting, Fang, Min, Zhang, Luo, Duo, Shuguang, Guo, Xuejiang, Li, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9184850/
https://www.ncbi.nlm.nih.gov/pubmed/35674692
http://dx.doi.org/10.1083/jcb.202108015
Descripción
Sumario:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal pathogen of the ongoing global pandemic of coronavirus disease 2019 (COVID-19). Loss of smell and taste are symptoms of COVID-19, and may be related to cilia dysfunction. Here, we found that the SARS-CoV-2 ORF10 increases the overall E3 ligase activity of the CUL2(ZYG11B) complex by interacting with ZYG11B. Enhanced CUL2(ZYG11B) activity by ORF10 causes increased ubiquitination and subsequent proteasome-mediated degradation of an intraflagellar transport (IFT) complex B protein, IFT46, thereby impairing both cilia biogenesis and maintenance. Further, we show that exposure of the respiratory tract of hACE2 mice to SARS-CoV-2 or SARS-CoV-2 ORF10 alone results in cilia-dysfunction-related phenotypes, and the ORF10 expression in primary human nasal epithelial cells (HNECs) also caused a rapid loss of the ciliary layer. Our study demonstrates how SARS-CoV-2 ORF10 hijacks CUL2(ZYG11B) to eliminate IFT46 and leads to cilia dysfunction, thereby offering a powerful etiopathological explanation for how SARS-CoV-2 causes multiple cilia-dysfunction-related symptoms specific to COVID-19.