What question did this study set out to answer?

This study aims to understand how SARS-CoV-2 nsp3 facilitates viral RNA contact with cellular membranes for replication.

May 26, 2026Cell & Bioscience0 citationsOpen Access

The transmembrane segments of SARS-CoV-2 nsp3 govern viral intracellular trafficking

MCManqi CaoSun Yat-sen University LQLang QinSun Yat-sen University HZHaitao ZhangWannan Medical College

Key Points

This study aims to understand how SARS-CoV-2 nsp3 facilitates viral RNA contact with cellular membranes for replication.
Demonstrated the role of the first transmembrane helix of nsp3 in ER insertion via SEC61A1.
Used deletion and proline substitution of key residues to assess effects on viral replication.
Tested a 24-residue peptide (Y24) and AAV9-delivered A20-2 peptide in mouse models for viral RNA reduction.
Key residue substitution trapped viral RNA in the cytosol, severely impairing viral replication.
Peptide Y24 effectively inhibited viral replication in experimental settings.
AAV9-delivered A20-2 significantly reduced lung viral RNA and pathology in mice.

Abstract

After entry, coronaviruses deliver their genomic RNA to the ER-Golgi intermediate compartment to build replication organelles, yet how the RNA first contacts membranes is unclear. Here, we demonstrate that the first transmembrane helix of nsp3 serves as an address code, inserting into the ER via SEC61A1 during translation and is then escorted to the ERGIC by the COPII factors SAR1A and LMAN1. Deletion or proline substitution of key residues in this helix trapped the RNA in the cytosol and crippled viral replication. A 24-residue peptide (Y24) modeled on the helix inhibited viral replication, and AAV9-delivered A20-2 peptide reduced lung viral RNA and pathology in mice. This host-targeted approach offers a potential broad-spectrum strategy against emerging coronaviruses.

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