Elucidating the role of SERINC5 in SARS-CoV-2 infection

最近，一种与严重肺炎相关的病毒性病原体被确定为造成全球大流行的原因，造成200多万人死亡。这种病毒病原体后来被归类为冠状病毒，随后被命名为严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）。目前，关于SARS-CoV-2感染及其相关细胞因素的信息缺乏。鉴定针对SARS-CoV-2感染的宿主因子并阐明其作用机制对于开发SARS-CoV-2治疗药物至关重要。最近的研究表明，由5个多通跨膜蛋白（SERINC1-5）组成的丝氨酸结合子（SERINC）蛋白家族在逆转录病毒进入中起关键作用，但SERINC因子在包括SARS-CoV-2感染在内的其他病毒感染中的作用目前尚不清楚。本研究旨在探讨SERINC5对SARS-CoV-2感染的影响。本提案的目的是为SERINC5对SARS-CoV-2进入的影响提供机制证据，因为很多时候，宿主因子使用不同的机制来限制属于不同病毒科的病毒。先前的研究表明，人类免疫缺陷病毒（HIV）受到SERINC5的有效限制，其机制尚未完全阐明。然而，HIV编码一种辅助蛋白Nef，它抵消了SERINC5的有害作用。在其他逆转录病毒中也发现了类似的病毒蛋白，这证明了SERINC5在逆转录病毒感染中的重要性。因此，该建议的另一个方面是确定针对SERINC5的SARS-CoV-2编码因子及其用于抵消SERINC5的机制。这项研究将为了解针对SARS-CoV-2的新型宿主因子的作用提供急需的见解，这非常重要，因为对针对SARS-CoV-2的宿主因子的机制了解并不多。此外，人们对SARS-CoV-2蛋白的作用以及它们如何调节宿主细胞知之甚少；因此，本提案的发现将为SARS-CoV-2编码因子的功能提供有价值的信息。最后，限制SARS-CoV-2感染的宿主因子的发现可能会扩大开发SARS-CoV-2抗病毒药物的潜在药物靶点范围。

A viral pathogen associated with severe pneumonia was recently identified as the cause of a global pandemic that has resulted in the death of over two million people. This viral pathogen was later classified as a coronavirus that was subsequently named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Currently, there is a paucity of information regarding SARS-CoV-2 infection and the cellular factors associated with it. The identification of host factors that target SARS-CoV-2 infection and the elucidation of their mechanism of action is critical for the development of SARS-CoV-2 therapeutics. It was recently shown that the Serine Incorporator (SERINC) protein family, which is comprised by 5 multipass transmembrane proteins (SERINC1-5) plays a critical role in retroviral entry, yet the role of SERINC factors on other viral infections including SARS-CoV-2 infection is currently unknown. This proposal investigates the effect of SERINC5 on SARS-CoV-2 infection. The goal of this proposal is to provide mechanistic evidence on the effect of SERINC5 on SARS-CoV-2 entry, as many times, host factors use different mechanisms to restrict viruses that belong to different viral families. Previous research has shown that human immunodeficiency virus (HIV) is potently restricted by SERINC5 in a mechanism that has not been fully elucidated. However, HIV encodes an accessory protein, Nef, which counteracts the deleterious effect of SERINC5. Similar viral proteins have been identified in other retroviruses, which demonstrates the importance of SERINC5 in retrovirus infection. Hence another aspect of this proposal is to determine a SARS-CoV-2 encoded factor that targets SERINC5 and the mechanism it utilizes to counteract SERINC5. This study will provide much needed insight into the role of a novel host factor that targets SARS- CoV-2, which is of great importance as there is not a lot of mechanistic understanding of host factors that target SARS-CoV-2. Moreover, little is known about the role of SARS-CoV-2 proteins and how they modulate the host cell; hence, the findings of this proposal will provide valuable information regarding the function of SARS-CoV-2 encoded factors. Finally, the discovery of host factors that restrict SARS-CoV-2 infection may expand the gamut of potential drug targets for the development of SARS-CoV-2 antivirals.