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SARS-CoV-2 RBD binds to kidney injury molecule-1, which is markedly expressed in the proximal tubule upon kidney injury

Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is a systemic multiple-organ disease characterized by a broad spectrum of clinical manifestations. Apart from the lung, multiorgan manifestations of COVID-19 show a high vulnerability of the kidney to the SARS-CoV-2. Patients with COVID-19 have a high incidence of acute kidney injury, and renal dysfunctions are strongly associated with high mortality. The infective SARS-CoV-2 has been confirmed in the kidneys, especially renal epithelial cells. In this study, the Chinese researchers investigated whether SARS-CoV-2 binds to kidney injury molecule-1 (KIM1). 

KIM1 is a type-1 transmembrane protein that is not normally present but is drastically upregulated in the apical membrane of the proximal tubule only upon kidney injury. It consists of the immunoglobulin variable Ig-like (IgV) domain, the mucin domain, the transmembrane domain, and the cytosolic domain. The IgV domain is required for virus binding and internalization, as shown by the entry of Ebola and dengue viruses.

SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus. Its genome encodes four structural proteins, namely the spike (S), envelope (E), nucleocapsid (N), and membrane (M) protein. The S protein appears to be a major pathogenic factor that contributes to the unique pathogenesis of SARS-CoV-2. The S protein is a glycosylated homotrimer with each monomer composed of subunits S1 and S2, separated by host cell proteases. The S1 domain comprises the N-terminal domain (NTD), the receptor binding domain (RBD) with a receptor binding motif (RBM), and two C-terminal domains. The RBD in the S1 subunit is a short immunogenic fragment that facilitates the S protein binding to the host cell angiotensin-converting enzyme 2 receptor (ACE2)

ACE2 is enriched in the kidney as the target for SARS-CoV2, but, the authors speculated that additional receptors may mediate the renal infection. The co-expression of KIM1 and ACE2 in the kidney, colon, rectum, testis, and gallbladder, all of which are the target organs of SARS-CoV-2, suggests a close association between KIM1 and COVID-19 manifestations.

 

 

 

About the study

The results showed that the RBD of the SARS-CoV-2 S protein binds to KIM1 and that the immunoglobulin variable Ig-like (IgV) domain of KIM1 plays a key role in this recognition. SARS-CoV-2-RBD showed the highest binding affinity to KIM1 compared to SARS-CoV-RBD and MERS-COV-RBD, although SARS-CoV-RBD and SARS-CoV-2-RBD target the same binding pocket in the IgV domain. 

Fluorescein isothiocyanate labeling, used to track SARS-CoV-2-RBD in human cells, demonstrated a decreased binding signal on the surface of human renal cells when KIM1 was knocked out, and a more intense signal when KIM1 was overexpressed. The restoration of full-length KIM1 and the overexpression of IgV led to the restoration of binding signals on the surface of human renal cells with KIM1 knockout. These data confirm the crucial role of the IgV domain in mediating SARS-CoV-2 attachment to renal cells. 

The coimmunoprecipitation assay confirmed the binding between SARS-CoV-2 RBD and KIM1. The fluorescence spectrophotometry and confocal microscopy identified an intracellular interaction between KIM1 and RBD. Knocking out KIM1 or deleting the IgV domain abolished the binding between KIM1 and SARS-CoV-2 RBD, indicating that the IgV domain is crucial in mediating the interaction between KIM1 and SARS-CoV-2. Antagonist peptide AP2 that competitively binds with SARS-CoV-2 RBD significantly inhibited the interaction between SARS-CoV-2 and KIM1 and reduced the attachment of the RBD to the cell surface.

The interaction of Phe338, Val367, Ser371, Phe374, and Trp436 of SARS-CoV-2 RBD with Leu54, Phe55, Gln58, Trp112, and Phe113 of KIM1 IgV resulted in a combined binding free energy of −35.64 kcal/mol, which is lower than that of SARS-CoV-2 RBD and ACE2 (−50.60 kcal/mol). The authors speculated that RBD binds to KIM1 and ACE2 by distinct binding regions and that KIM1 and ACE2 may synergistically mediate the invasion of SARS-CoV-2.

 

Conclusion

This study has shown that KIM1, a type-1 transmembrane protein, which is highly expressed only upon kidney injury, has a significant role in the renal tropism of SARS-CoV-2, as a potential receptor for SARS-CoV-2. Compared to SARS-CoV RBD and MERS-COV RBD, SARS-CoV-2 RBD also showed the highest binding affinity for KIM1.

Notably, the authors proposed a “vicious cycle” model, which may explain the renal tropism of SARS-CoV-2 in COVID-19 patients. During the initial stage of SARS-CoV-2 invasion, ACE2 is the primary target because of its higher physiological level and binding affinity. However, after the onset of acute kidney injury caused by the virus and significant upregulation of KIM1, the ACE2, and KIM1 may synergistically mediate SARS-CoV-2 invasion and rapidly promote the infection. Consequently, this “vicious cycle” further exacerbates a kidney injury.

 

 

This article was published in the Journal of Molecular Cell Biology.

 

Journal Reference

Yang C, Zhang Y, Zeng X et al. Kidney injury molecule-1 is a potential receptor for SARS-CoV-2. Journal of Molecular Cell Biology (2021), 13(3), 185196. (Open Access)   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928767/

 

 

 

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