Contribution of Syndecans to the Cellular Entry of SARS-CoV-2.

Anett Hudák,Annamária Letoha,László Szilák,Tamás Letoha

doi:10.3390/ijms22105336

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel emerging pathogen causing an unprecedented pandemic in 21st century medicine. Due to the significant health and economic burden of the current SARS-CoV-2 outbreak, there is a huge unmet medical need for novel interventions effectively blocking SARS-CoV-2 infection. Unknown details of SARS-CoV-2 cellular biology hamper the development of potent and highly specific SARS-CoV-2 therapeutics. Angiotensin-converting enzyme-2 (ACE2) has been reported to be the primary receptor for SARS-CoV-2 cellular entry. However, emerging scientific evidence suggests the involvement of additional membrane proteins, such as heparan sulfate proteoglycans, in SARS-CoV-2 internalization. Here, we report that syndecans, the evolutionarily conserved family of transmembrane proteoglycans, facilitate the cellular entry of SARS-CoV-2. Among syndecans, the lung abundant syndecan-4 was the most efficient in mediating SARS-CoV-2 uptake. The S1 subunit of the SARS-CoV-2 spike protein plays a dominant role in the virus’s interactions with syndecans. Besides the polyanionic heparan sulfate chains, other parts of the syndecan ectodomain, such as the cell-binding domain, also contribute to the interaction with SARS-CoV-2. During virus internalization, syndecans colocalize with ACE2, suggesting a jointly shared internalization pathway. Both ACE2 and syndecan inhibitors exhibited significant efficacy in reducing the cellular entry of SARS-CoV-2, thus supporting the complex nature of internalization. Data obtained on syndecan specific in vitro assays present syndecans as novel cellular targets of SARS-CoV-2 and offer molecularly precise yet simple strategies to overcome the complex nature of SARS-CoV-2 infection.

Highlights

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a betacoronavirus initially emerging in China and rapidly spreading throughout the world, becoming a significant threat to human health [1,2,3,4,5,6,7,8]
SDC isoforms were created in K562 cells, a human myeloid leukemia cell line lacking endogenous heparan sulfate proteoglycans (HSPGs) except for minor amounts of endogenous betaglycan [55,69]
As heparan sulfate (HS) has already been established as a primary binding site for several viruses [52], including SARS-CoV [32], stable SDC transfectants created in K562 cells were standardized according to their HS content (Supplementary Figure S2) [45,46] (it is worth noting that SDC transfection did not induce statistically significant changes in Angiotensin-converting enzyme-2 (ACE2) expression (Supplementary Figure S3))

Summary

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a betacoronavirus initially emerging in China and rapidly spreading throughout the world, becoming a significant threat to human health [1,2,3,4,5,6,7,8]. Caused by SARS-CoV-2 infection, the coronavirus disease 2019 (COVID-19) poses specific challenges for adequate and effective treatment to avoid the onset of severe clinical manifestations [10]. There is no specific antiviral therapy against SARS-CoV-2 infection [11]. Among the applied anti-COVID-19 therapeutics, remdesivir, an antiviral agent originally developed against Ebola infection, shows one of the most promising clinical efficacy in attenuating the severity of COVID-19 [14,15]. Given the high mortality despite remdesivir, novel and more efficient combinatory strategies should be developed to improve patient outcomes in COVID-19 [15]

Methods

Results

Conclusion