SARS-CoV-2 ORF10 impairs cilia by enhancing CUL2ZYG11B activity
Liying Wang, Chao Liu, Bo Yang, Haotian Zhang, Jian Jiao, Ruidan Zhang, Shu‐Jun Liu, Sai Jin Xiao, Yinghong Chen, Bo Liu, Yanjie Ma, Xuefeng Duan, Yueshuai Guo, Mengmeng Guo, Bingbing Wu, Xiangdong Wang, Xingxu Huang, Haitao Yang, Yaoting Gui, Min Fang, Luo Zhang, Shuguang Duo, Xuejiang Guo, Wei Li
Abstract
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 CUL2ZYG11B complex by interacting with ZYG11B. Enhanced CUL2ZYG11B 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 CUL2ZYG11B 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.