SARS-CoV-2 ORF10 impairs cilia by enhancing CUL2ZYG11B activity

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 new identified symptoms of COVID‐19, and both of these are related to cilia dysfunction. However, the pathological mechanisms are still unknown. Here, we found that SARS-CoV-2 ORF10 increases the overall E3 ligase activity of the CUL2ZYG11B complex by acting as a binding nexus for both ZYG11B and UBE2D1. Enhanced CUL2ZYG11B activity by ORF10 causes increased ubiquitination and subsequent proteasome-mediated degradation of an intraflagellar transport (IFT) complex B protein, IFT46, thereby impairing the cilia biogenesis and maintenance. Furthermore, we show that exposure of the respiratory tract of hACE2 humanized mice to SARS-CoV-2 ORF10 (using lentivirus pseuodotyped particles) results in multiple pathogenic phenotypes, including an obviously damaged cilia layer in the trachea, interstitial congestion, epithelial damage, and per

ORGANISM(S): Homo Sapiens

SUBMITTER: Xuejiang Guo  

PROVIDER: PXD031842 | iProX | Wed Feb 23 00:00:00 GMT 2022

REPOSITORIES: iProX