New Viral Defense Mechanism

SUMMARY

Proteolytic cleavage by furin-like proteases is a crucial first step in the posttranslational modification of various glycoproteins found in enveloped emerging viruses, such as SARS-CoV-2 and highly pathogenic avian influenza A viruses (IAV). Here, Prof. Schmolke's team explored the capacity of host cell proteins identified by cell surface proximity ligation to limit the proteolytic cleavage of the SARS-CoV-2 spike and the IAV H5N1 hemagglutinin (HA). When co-expressed with recombinant SARS-CoV-2 spike protein, Prom1, Axl, and Ly75 suppress its proteolytic cleavage, whereas cleavage of HA was only reduced by Prom1. Co-immunoprecipitation assays suggest that Axl and Prom1 may form a complex with furin. Alteration of Prom1, Axl and Ly75 expression levels in Calu3 cells affected the entry of SARS-CoV-2 S pseudotyped VLP and to a lesser extent, SARS-CoV-2 virions. In contrast, Prom1 levels did not affect the entry of H5N1 VLPs or H5N1 virions. These data highlight the differential capacity of SARS-CoV-2 and IAV H5N1 to cope with newly identified host restriction factors of furin activity.

Read full article: https://doi.org/10.1038/s41598-025-11164-x

WHY IS THIS IMPORTANT?

Successful viral entry often depends on host proteases that activate viral surface proteins. For SARS-CoV-2, the enzyme furin cleaves the spike protein to enable fusion with host membranes. In this study, GCIR researchers identified host cell proteins, Prom1, Axl, and Ly75, that can interfere with furin’s activity. When expressed, these proteins reduced the cleavage of the SARS-CoV-2 spike, limiting viral entry. Interestingly, their effect on H5N1 influenza was weaker, suggesting that different viruses rely on proteases in distinct ways. These findings highlight natural host restriction mechanisms that could inform the design of antiviral strategies targeting furin-dependent pathways.

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