tetano
Editor, Senior Moderator
JCI Insight
. 2026 Feb 23;11(4):e185739.
doi: 10.1172/jci.insight.185739.
Unbiased cleavage site prediction uncovers viral antagonism of host innate immunity by SARS-CoV-2 3C-like protease
Nora Yucel[SUP] 1 [/SUP], Silvia Marchiano[SUP] 2 3 4 [/SUP], Evan Tchelepi[SUP] 5 [/SUP], Germana Paterlini[SUP] 6 [/SUP], Ivan A Kuznetsov[SUP] 1 [/SUP], Kristina Li[SUP] 1 [/SUP], Quentin McAfee[SUP] 1 [/SUP], Nehaar Nimmagadda[SUP] 1 [/SUP], Andy Ren[SUP] 1 [/SUP], Sam Shi[SUP] 1 [/SUP], Alyssa Grogan[SUP] 7 [/SUP], Aikaterini Kontrogianni-Konstantopoulos[SUP] 7 [/SUP], Charles Murry[SUP] 2 3 4 8 9 10 [/SUP], Zoltan Arany[SUP] 1 [/SUP]
Affiliations
How SARS-CoV-2 causes a wide range of clinical manifestations and disease severity remains poorly understood. SARS-CoV-2 encodes 2 proteases (3CLPro and PLPro), vital for viral production, but also promiscuous with respect to host protein targets. Pharmacological inhibition of 3CLPro markedly reduced hospitalization and death in Phase 2/3 clinical studies. Here, we develop a bioinformatic algorithm, leveraging experimental data from SARS-CoV, to predict host cleavage targets of 3CLPro. We capture targets of 3CLPro described previously for SARS-CoV-2, as well as thousands of putative targets. We validate numerous targets cleaved during infection, including the giant sarcomeric protein obscurin and the innate immune protein OAS1. A long form of OAS1, p46, has been associated in numerous GWAS studies with lesser COVID disease severity. We show that 3CLPro cleaves p46 OAS1 immediately upstream of a known prenylation domain, relocalizing OAS1 from subcellular membranes to the cytosol, rendering it akin to the nonprotective, cytosolic p42 isoform. Similar OAS1 relocalization occurs upon infection by SARS-CoV-2. Our data provide a high-throughput resource to identify putative host cleavage targets of 3CLPro and reveal a mechanism by which SARS-CoV-2 antagonizes host innate immunity in individuals with the protective p46 isoform of OAS1.
Keywords: COVID-19; Cardiovascular disease; Innate immunity; Proteases; Virology.
. 2026 Feb 23;11(4):e185739.
doi: 10.1172/jci.insight.185739.
Unbiased cleavage site prediction uncovers viral antagonism of host innate immunity by SARS-CoV-2 3C-like protease
Nora Yucel[SUP] 1 [/SUP], Silvia Marchiano[SUP] 2 3 4 [/SUP], Evan Tchelepi[SUP] 5 [/SUP], Germana Paterlini[SUP] 6 [/SUP], Ivan A Kuznetsov[SUP] 1 [/SUP], Kristina Li[SUP] 1 [/SUP], Quentin McAfee[SUP] 1 [/SUP], Nehaar Nimmagadda[SUP] 1 [/SUP], Andy Ren[SUP] 1 [/SUP], Sam Shi[SUP] 1 [/SUP], Alyssa Grogan[SUP] 7 [/SUP], Aikaterini Kontrogianni-Konstantopoulos[SUP] 7 [/SUP], Charles Murry[SUP] 2 3 4 8 9 10 [/SUP], Zoltan Arany[SUP] 1 [/SUP]
Affiliations
- PMID: 41729072
- DOI: 10.1172/jci.insight.185739
How SARS-CoV-2 causes a wide range of clinical manifestations and disease severity remains poorly understood. SARS-CoV-2 encodes 2 proteases (3CLPro and PLPro), vital for viral production, but also promiscuous with respect to host protein targets. Pharmacological inhibition of 3CLPro markedly reduced hospitalization and death in Phase 2/3 clinical studies. Here, we develop a bioinformatic algorithm, leveraging experimental data from SARS-CoV, to predict host cleavage targets of 3CLPro. We capture targets of 3CLPro described previously for SARS-CoV-2, as well as thousands of putative targets. We validate numerous targets cleaved during infection, including the giant sarcomeric protein obscurin and the innate immune protein OAS1. A long form of OAS1, p46, has been associated in numerous GWAS studies with lesser COVID disease severity. We show that 3CLPro cleaves p46 OAS1 immediately upstream of a known prenylation domain, relocalizing OAS1 from subcellular membranes to the cytosol, rendering it akin to the nonprotective, cytosolic p42 isoform. Similar OAS1 relocalization occurs upon infection by SARS-CoV-2. Our data provide a high-throughput resource to identify putative host cleavage targets of 3CLPro and reveal a mechanism by which SARS-CoV-2 antagonizes host innate immunity in individuals with the protective p46 isoform of OAS1.
Keywords: COVID-19; Cardiovascular disease; Innate immunity; Proteases; Virology.