SARS-CoV-2 selectively mimics a cleavable peptide of human ENaC in a strategic hijack of host proteolytic machinery

Puranik, Arjun; Aravamudan, Murali; Venkatakrishnan, AJ; Soundararajan, Venky

doi:10.1101/2020.04.29.069476

Cited by 9 publications

(10 citation statements)

References 16 publications

(14 reference statements)

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“…The furin protease emerges as a likely candidate, since the SARS-CoV-2 S-protein contains four redundant furin cleavage sites that are absent in the SARS-CoV ( 18 ). In addition, the new coronavirus has an S1/S2 cleavage site (RRARSVAS) similar to a host furin-cleavable peptide in epithelial sodium channel α-subunit (ENaC-α) ( 19 ). Moreover, sequence-based prediction studies suggest a more efficient cleavage of the SARS-CoV-2 than the SARS-CoV S-protein by furin ( 18 , 20 ).…”

Section: Sars-cov-2 Infectionmentioning

confidence: 99%

ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19

2020

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The Coronavirus Disease 2019 (COVID-19) has already caused hundreds of thousands of deaths worldwide in a few months. Cardiovascular disease, hypertension, diabetes and chronic lung disease have been identified as the main COVID-19 comorbidities. Moreover, despite similar infection rates between men and women, the most severe course of the disease is higher in elderly and co-morbid male patients. Therefore, the occurrence of specific comorbidities associated with renin-angiotensin system (RAS) imbalance mediated by the interaction between angiotensin-converting enzyme 2 (ACE2) and desintegrin and metalloproteinase domain 17 (ADAM17), along with specific genetic factors mainly associated with type II transmembrane serine protease (TMPRSS2) expression, could be decisive for the clinical outcome of COVID-19. Indeed, the exacerbated ADAM17-mediated ACE2, TNF-a, and IL-6R secretion emerges as a possible underlying mechanism for the acute inflammatory immune response and the activation of the coagulation cascade. Therefore, in this review, we focus on the main pathophysiological aspects of ACE2, ADAM17, and TMPRSS2 host proteins in COVID-19. Additionally, we discuss a possible mechanism to explain the deleterious effect of ADAM17 and TMPRSS2 over-activation in the COVID-19 outcome.

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Section: Sars-cov-2 Infectionmentioning

confidence: 99%

ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19

2020

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“…However, scientific evidence shows that endocytosis of SARS-CoV also occurs through a novel, clathrin- and caveolae-independent endocytic pathway, mediated by attachment to cell surface heparan sulfate proteoglycans (HSPGs) [ 29 , 30 , 31 , 32 ]. Meanwhile, it has also been revealed that the S1 subunit of the SARS-CoV-2 spike protein, the subunit responsible for cellular attachment, contains the heparin-binding core motif PRRAR [ 33 , 34 , 35 , 36 ] ( Supplementary Figure S1 ). According to the most recent SARS-CoV-2 infection models, viral attachment and infection involve the formation of a complex between heparan sulfate (HS) and ACE2 [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

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

Hudák¹,

Letoha

Szilák

et al. 2021

IJMS

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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.

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“…Another very recent ndings of also showed heparin effectively blocking SARS-CoV-2 invasion into Vero cells 88 . It has to be noted that the primary sequence of spikeS1 (namely Pro681 -Arg685) contains the heparin-binding core motif PRRAR [33][34][35] ( Supplementary Fig. S1).…”

Section: Discussionmentioning

confidence: 99%

“…However, scienti c evidence shows that endocytosis of SARS-CoV also occurs through a novel, clathrinand caveolae-independent endocytic pathway, mediated by attachment to cell surface heparan sulfate proteoglycans (HSPGs) [29][30][31][32] . Meanwhile, it has been also revealed that the S1 subunit of the SARS-CoV-2 spike protein, the subunit responsible for cellular attachment, contains the heparin-binding core motif PRRAR [33][34][35][36] ( Supplementary Fig. S1).…”

Section: Development Of E Cient Therapeutics Against Covid-19 Is Hampmentioning

confidence: 99%

Contribution of syndecans to the cellular entry of SARS-CoV-2

Hudák

Szilák

Letoha

2020

Preprint

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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 significantly 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, syndecan-4 was the most efficient in mediating SARS-CoV-2 uptake, yet overexpression of other isoforms, including the neuronal syndecan-3, also increased SARS-CoV-2 internalization. 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 - the established binding sites for several viruses - 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 cellular entry of SARS-CoV-2, thus supporting the complex nature of internalization. Among these inhibitors, a peptide compromising the spike protein’s heparin-binding PRRAR motif significantly reduced SARS-CoV-2 cellular uptake, highlighting the need to go beyond the ACE2 paradigm for developing efficient therapeutics against SARS-CoV-2. Data obtained on syndecan specific in vitro assays present syndecans as novel cellular targets of SARS-CoV-2 and offers molecularly precise, yet simple strategies in overcoming the complex nature of SARS-CoV-2 infection.

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SARS-CoV-2 selectively mimics a cleavable peptide of human ENaC in a strategic hijack of host proteolytic machinery

Cited by 9 publications

References 16 publications

ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19

ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19

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

Contribution of syndecans to the cellular entry of SARS-CoV-2

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