A Comprehensive Review of Coronavirus Non-Structure Protein 6 on Structure, Functions, Mechanisms and Its Implications for Antiviral Research

Coronaviruses encode a variety of non-structural proteins (NSPs) that collectively mediate viral genome replication, transcription and remodeling of the host cellular microenvironment. As a highly conserved transmembrane protein, non-structural protein 6 (NSP6) predominantly localizes to the endoplasmic reticulum. Through interactions with other viral proteins and host factors, NSP6 participates in multiple pivotal processes, including the formation and stabilization of double-membrane vesicles (DMVs), reprogramming of lipid metabolism, blockade of autophagic flux, and evasion of innate immunity. Recent advances in structural biology and research on virus–host interactions have further elucidated the essential roles of NSP6 throughout the viral life cycle. Mutations in NSP6 are closely associated with viral adaptability, transmissibility and pathogenicity. Herein, we comprehensively review the latest advances on the molecular structure, biological functions and mutation hotspots of coronavirus NSP6, as well as its implications for antiviral research. This review aims to provide a theoretical basis for further dissecting the pathogenic mechanisms of coronaviruses and developing broad-spectrum antiviral drugs.