Datta Gaurav, Rezagholizadeh Neda, Hasler Wendie A, Khan Nabab, Chen Xuesong
Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58203, USA.
iScience. 2024 Jun 27;27(7):110387. doi: 10.1016/j.isci.2024.110387. eCollection 2024 Jul 19.
SARS-CoV-2 viral entry into host cells depends on the cleavage of spike (S) protein into S1 and S2 proteins. Such proteolytic cleavage by furin results in the exposure of a multibasic motif on S1, which is critical for SARS-CoV-2 viral infection and transmission; however, how such a multibasic motif contributes to the infection of SARS-CoV-2 remains elusive. Here, we demonstrate that the multibasic motif on S1 is critical for its interaction with SLC38A9, an endolysosome-resident arginine sensor. SLC38A9 knockdown prevents S1-induced endolysosome de-acidification and blocks the S protein-mediated entry of pseudo-SARS-CoV-2 in Calu-3, U87MG, Caco-2, and A549 cells. Our findings provide a novel mechanism in regulating SARS-CoV-2 viral entry; S1 present in endolysosome lumen could interact with SLC38A9, which mediates S1-induced endolysosome de-acidification and dysfunction, facilitating the escape of SARS-CoV-2 from endolysosomes and enhancing viral entry.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）进入宿主细胞依赖于刺突（S）蛋白裂解为S1和S2蛋白。弗林蛋白酶进行的这种蛋白水解切割导致S1上一个多碱性基序的暴露，这对SARS-CoV-2病毒感染和传播至关重要；然而，这样一个多碱性基序如何促进SARS-CoV-2的感染仍不清楚。在此，我们证明S1上的多碱性基序对其与SLC38A9（一种定位于内溶酶体的精氨酸传感器）的相互作用至关重要。敲低SLC38A9可防止S1诱导的内溶酶体去酸化，并阻断S蛋白介导的伪SARS-CoV-2进入Calu-3、U87MG、Caco-2和A549细胞。我们的研究结果提供了一种调节SARS-CoV-2病毒进入的新机制；存在于内溶酶体腔中的S1可与SLC38A9相互作用，后者介导S1诱导的内溶酶体去酸化和功能障碍，促进SARS-CoV-2从内溶酶体中逃逸并增强病毒进入。
