SARS-CoV-2 Spike Protein Interacts with Multiple Innate Immune Receptors

Gao, Chao; Zeng, Junwei; Jia, Nan; Stavenhagen, Kathrin; Matsumoto, Yasuyuki; Zhang, Hua; Jiang, Li; Hume, Adam J.; Mühlberger, Elke; Die, Irma van; Kwan, Julian; Tantisira, Kelan G.; Emili, Andrew; Cummings, Richard D.

doi:10.1101/2020.07.29.227462

Cited by 106 publications

(144 citation statements)

References 69 publications

(83 reference statements)

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“…Several structural analyses of the SARS-CoV-2 S protein glycans have been reported, showing the presence of a large fraction of mature N- and O-glycans, alongside immature forms. However, none of these studies described the expression of blood group antigens on the S protein ( Gao et al, 2020 , Sanda et al, 2020 , Shajahan et al, 2020 , Sun et al, 2020 , Watanabe et al, 2020 ). Yet, all analyses were performed on recombinant S protein produced in HEK-293T cells which do not express blood group antigens, unlike epithelial cells of the larynx and the bronchial mucosa where infectious viral particles are likely produced.…”

Section: Resultsmentioning

confidence: 99%

Covid-19 and blood groups: ABO antibody levels may also matter

Deleers¹,

Breiman²,

Daubie³

et al. 2021

International Journal of Infectious Diseases

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Section: Resultsmentioning

confidence: 99%

Covid-19 and blood groups: ABO antibody levels may also matter

Deleers¹,

Breiman²,

Daubie³

et al. 2021

International Journal of Infectious Diseases

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“…Since the binding, internalization and infection of SARS-CoV-2 was greatly reduced but not completely abolished in AXL-KO H1299 cells, additional receptor(s) other than AXL and ACE2 which mediates viral entry may exist. Several proteins have been recently identified to interact with SARS-CoV-2 S, including lectin receptors and multiple innate immune receptors, 40,41 heparan sulfate, 42,43 neuropilins, 44,45 asialoglycoprotein receptor 1 and Kremen protein 1. 46 However, most of them lack virology-related evidence to support their roles as SARS-CoV-2 entry factors.…”

Section: Discussionmentioning

confidence: 99%

AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells

et al. 2021

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The current coronavirus disease 2019 (COVID-19) pandemic presents a global public health challenge. The viral pathogen responsible, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), binds to the host receptor ACE2 through its spike (S) glycoprotein, which mediates membrane fusion and viral entry. Although the role of ACE2 as a receptor for SARS-CoV-2 is clear, studies have shown that ACE2 expression is extremely low in various human tissues, especially in the respiratory tract. Thus, other host receptors and/or co-receptors that promote the entry of SARS-CoV-2 into cells of the respiratory system may exist. In this study, we found that the tyrosine-protein kinase receptor UFO (AXL) specifically interacts with the N-terminal domain of SARS-CoV-2 S. Using both a SARS-CoV-2 virus pseudotype and authentic SARS-CoV-2, we found that overexpression of AXL in HEK293T cells promotes SARS-CoV-2 entry as efficiently as overexpression of ACE2, while knocking out AXL significantly reduces SARS-CoV-2 infection in H1299 pulmonary cells and in human primary lung epithelial cells. Soluble human recombinant AXL blocks SARS-CoV-2 infection in cells expressing high levels of AXL. The AXL expression level is well correlated with SARS-CoV-2 S level in bronchoalveolar lavage fluid cells from COVID-19 patients. Taken together, our findings suggest that AXL is a novel candidate receptor for SARS-CoV-2 which may play an important role in promoting viral infection of the human respiratory system and indicate that it is a potential target for future clinical intervention strategies.

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“…The possibility of additional receptors should not be excluded. Earlier work with SARS-CoV has shown that several plasma membrane lectins can act as co-receptors (32), and in SARS-CoV-2, lectins expressed by innate immune cells bind the spike protein with high affinity and can promote viral entry (214). The cytosolic tails of a number of the lectin receptors are substrates of tyrosine kinases.…”

Section: Discussionmentioning

confidence: 99%

Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications

et al. 2021

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The first reported receptor for SARS-CoV-2 on host cells was the angiotensin-converting enzyme 2 (ACE2). However, the viral spike protein also has an RGD motif, suggesting that cell surface integrins may be co-receptors. We examined the sequences of ACE2 and integrins with the Eukaryotic Linear Motif (ELM) resource and identified candidate short linear motifs (SLiMs) in their short, unstructured, cytosolic tails with potential roles in endocytosis, membrane dynamics, autophagy, cytoskeleton, and cell signaling. These SLiM candidates are highly conserved in vertebrates and may interact with the μ2 subunit of the endocytosis-associated AP2 adaptor complex, as well as with various protein domains (namely, I-BAR, LC3, PDZ, PTB, and SH2) found in human signaling and regulatory proteins. Several motifs overlap in the tail sequences, suggesting that they may act as molecular switches, such as in response to tyrosine phosphorylation status. Candidate LC3-interacting region (LIR) motifs are present in the tails of integrin β3 and ACE2, suggesting that these proteins could directly recruit autophagy components. Our findings identify several molecular links and testable hypotheses that could uncover mechanisms of SARS-CoV-2 attachment, entry, and replication against which it may be possible to develop host-directed therapies that dampen viral infection and disease progression. Several of these SLiMs have now been validated to mediate the predicted peptide interactions.

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SARS-CoV-2 Spike Protein Interacts with Multiple Innate Immune Receptors

Cited by 106 publications

References 69 publications

Covid-19 and blood groups: ABO antibody levels may also matter

Covid-19 and blood groups: ABO antibody levels may also matter

AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells

Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications

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