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.

中文翻译：

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SARS-CoV-2 ORF10 通过增强 CUL2ZYG11B 活性损害纤毛

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 是 2019 年冠状病毒病 (COVID-19) 全球大流行的致病病原体。嗅觉和味觉丧失是 COVID-19 的症状，可能与纤毛功能障碍有关。在这里，我们发现 SARS-CoV-2 ORF10 通过与 ZYG11B 相互作用增加了 CUL2ZYG11B 复合物的整体 E3 连接酶活性。 ORF10 增强的 CUL2ZYG11B 活性导致泛素化增加，随后蛋白酶体介导的鞭毛内转运 (IFT) 复合物 B 蛋白 IFT46 降解，从而损害纤毛的生物发生和维持。此外，我们还发现，hACE2 小鼠的呼吸道暴露于 SARS-CoV-2 或单独的 SARS-CoV-2 ORF10 会导致纤毛功能障碍相关的表型，并且原代人鼻上皮细胞 (HNEC) 中的 ORF10 表达也会发生变化。导致睫状体层迅速丧失。我们的研究展示了 SARS-CoV-2 ORF10 如何劫持 CUL2ZYG11B 以消除 IFT46 并导致纤毛功能障碍，从而为 SARS-CoV-2 如何导致 COVID-19 特有的多种纤毛功能障碍相关症状提供强有力的病因病理学解释。