# Unbiased cleavage site prediction uncovers viral antagonism of host innate immunity by SARS-CoV-2 3C-like protease

## TL;DR

This study shows how the SARS-CoV-2 virus cuts host proteins, weakening the body's immune response and potentially worsening disease severity.

## Contribution

A novel bioinformatic algorithm predicts host cleavage targets of SARS-CoV-2 3CLPro and identifies a new mechanism of immune antagonism.

## Key findings

- 3CLPro cleaves the innate immune protein OAS1, relocalizing it from membranes to the cytosol.
- Cleavage of OAS1 p46 isoform reduces its protective effect against severe COVID.
- Thousands of putative host cleavage targets of 3CLPro were identified using an unbiased algorithm.

## Abstract

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.

We show here that the COVID virus can cause cutting of host proteins, thereby inhibiting host immunity against the virus.