Kidney injury molecule-1 is a potential receptor for SARS-CoV-2.
Kidney injury molecule-1 is a potential receptor for SARS-CoV-2.
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肾损伤分子 1 是 SARS-CoV-2 的潜在受体。
DOI：
10.1093/jmcb/mjab003
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发表时间：
2021-07-06
影响因子：
5.5
通讯作者：
Huang K
中科院分区：
文献类型：
--
作者：
Yang C;Zhang Y;Zeng X;Chen H;Chen Y;Yang D;Shen Z;Wang X;Liu X;Xiong M;Chen H;Huang K
COVID-19患者肾脏异常的发生率很高，这与预后不良和死亡率相关。在COVID-19患者的肾脏中鉴定出SARS-CoV-2，表明SARS-CoV-2具有肾嗜性。然而，肾脏中是否存在SARS-CoV-2的特异性靶点仍不清楚。在此，通过计算机模拟、免疫共沉淀、荧光共振能量转移、异硫氰酸荧光素标记和拮抗肽的合理设计，我们证明了肾损伤分子1（KIM 1），一种在肾损伤后显著上调的分子，与SARS-CoV-2的受体结合结构域（RBD）结合并促进其附着于细胞膜，KIM 1的免疫球蛋白可变Ig样（IG V）结构域在这种识别中起关键作用。SARS-CoV-2 RBD和KIM 1之间的相互作用被合理设计的KIM 1衍生多肽AP 2有效阻断。此外，我们的研究结果还表明KIM 1 IG V结构域与两种严重呼吸道传染病病原体SARS-CoV和MERS-CoV的RBD之间存在相互作用。总之，这些发现表明KIM 1是SARS-CoV-2和其他冠状病毒的新型受体。因此，我们认为KIM 1可能介导并加重了SARS-CoV-2的肾脏感染的恶性循环，KIM 1可以作为一个治疗靶点进一步探索。
COVID-19 patients present high incidence of kidney abnormalities, which are associated with poor prognosis and mortality. The identification of SARS-CoV-2 in the kidney of COVID-19 patients suggests renal tropism of SARS-CoV-2. However, whether there is a specific target of SARS-CoV-2 in the kidney remains unclear. Herein, by using in silico simulation, coimmunoprecipitation, fluorescence resonance energy transfer, fluorescein isothiocyanate labeling, and rational design of antagonist peptides, we demonstrate that kidney injury molecule-1 (KIM1), a molecule dramatically upregulated upon kidney injury, binds with the receptor-binding domain (RBD) of SARS-CoV-2 and facilitates its attachment to cell membrane, with the immunoglobulin variable Ig-like (Ig V) domain of KIM1 playing a key role in this recognition. The interaction between SARS-CoV-2 RBD and KIM1 is potently blockaded by a rationally designed KIM1-derived polypeptide AP2. In addition, our results also suggest interactions between KIM1 Ig V domain and the RBDs of SARS-CoV and MERS-CoV, pathogens of two severe infectious respiratory diseases. Together, these findings suggest KIM1 as a novel receptor for SARS-CoV-2 and other coronaviruses. We propose that KIM1 may thus mediate and exacerbate the renal infection of SARS-CoV-2 in a ‘vicious cycle’, and KIM1 could be further explored as a therapeutic target.