tetano
Editor, Senior Moderator
J Cell Biol
. 2022 Jul 4;221(7):e202108015.
doi: 10.1083/jcb.202108015. Epub 2022 Jun 8.
SARS-CoV-2 ORF10 impairs cilia by enhancing CUL2ZYG11B activity
Liying Wang[SUP] #[/SUP][SUP] 1 2 [/SUP], Chao Liu[SUP] #[/SUP][SUP] 1 2 [/SUP], Bo Yang[SUP] #[/SUP][SUP] 3 [/SUP], Haotian Zhang[SUP] #[/SUP][SUP] 4 [/SUP], Jian Jiao[SUP] #[/SUP][SUP] 5 6 [/SUP], Ruidan Zhang[SUP] 2 [/SUP], Shujun Liu[SUP] 7 [/SUP], Sai Xiao[SUP] 2 [/SUP], Yinghong Chen[SUP] 1 2 [/SUP], Bo Liu[SUP] 2 [/SUP], Yanjie Ma[SUP] 1 2 [/SUP], Xuefeng Duan[SUP] 8 [/SUP], Yueshuai Guo[SUP] 4 [/SUP], Mengmeng Guo[SUP] 1 2 [/SUP], Bingbing Wu[SUP] 1 2 [/SUP], Xiangdong Wang[SUP] 5 6 [/SUP], Xingxu Huang[SUP] 9 [/SUP], Haitao Yang[SUP] 10 [/SUP], Yaoting Gui[SUP] 3 [/SUP], Min Fang[SUP] 8 [/SUP], Luo Zhang[SUP] 5 6 [/SUP], Shuguang Duo[SUP] 7 [/SUP], Xuejiang Guo[SUP] 4 [/SUP], Wei Li[SUP] 1 2 [/SUP]
Affiliations
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.
. 2022 Jul 4;221(7):e202108015.
doi: 10.1083/jcb.202108015. Epub 2022 Jun 8.
SARS-CoV-2 ORF10 impairs cilia by enhancing CUL2ZYG11B activity
Liying Wang[SUP] #[/SUP][SUP] 1 2 [/SUP], Chao Liu[SUP] #[/SUP][SUP] 1 2 [/SUP], Bo Yang[SUP] #[/SUP][SUP] 3 [/SUP], Haotian Zhang[SUP] #[/SUP][SUP] 4 [/SUP], Jian Jiao[SUP] #[/SUP][SUP] 5 6 [/SUP], Ruidan Zhang[SUP] 2 [/SUP], Shujun Liu[SUP] 7 [/SUP], Sai Xiao[SUP] 2 [/SUP], Yinghong Chen[SUP] 1 2 [/SUP], Bo Liu[SUP] 2 [/SUP], Yanjie Ma[SUP] 1 2 [/SUP], Xuefeng Duan[SUP] 8 [/SUP], Yueshuai Guo[SUP] 4 [/SUP], Mengmeng Guo[SUP] 1 2 [/SUP], Bingbing Wu[SUP] 1 2 [/SUP], Xiangdong Wang[SUP] 5 6 [/SUP], Xingxu Huang[SUP] 9 [/SUP], Haitao Yang[SUP] 10 [/SUP], Yaoting Gui[SUP] 3 [/SUP], Min Fang[SUP] 8 [/SUP], Luo Zhang[SUP] 5 6 [/SUP], Shuguang Duo[SUP] 7 [/SUP], Xuejiang Guo[SUP] 4 [/SUP], Wei Li[SUP] 1 2 [/SUP]
Affiliations
- PMID: 35674692
- DOI: 10.1083/jcb.202108015
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.