Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped positive-stranded RNA virus, a member of the Betacoronavirus genus, and the causative agent of COVID-19.1,2,3 The SARS-CoV-2 genome contains approximately 30 kilobases and 14 open reading frames (ORFs) that encode four structural proteins: spike, envelope, membrane, and nucleocapsid, as well as 16 non-structural proteins and nine accessory factors.4 SARS-CoV-2 non-structural protein 4 (nsp4) is encoded within ORF1ab and is involved in host cell membrane reorganization via the formation of endoplasmic reticulum-derived double-membrane vesicles (DMVs), which act as replication organelles.4,5 Ectopic expression of SARS-CoV-2 nsp4 induces the unfolded protein response (UPR), increases the production of mitochondrial reactive oxygen species (mtROS), and decreases the mitochondrial membrane potential in, as well as induces mitochondrial DNA (mtDNA) release from, host cells in vitro.6,7 A tyrosine-to-isoleucine mutation at position 492 in nsp4 (nsp4T492I) is present in several SARS-CoV-2 variants, including Delta and Omicron, increases viral infectivity and the cleavage efficiency of main protease (Mpro), also known as 3C-like protease (3CLpro), enhances evasion of the host immune response, and is associated with decreased disease severity.8WARNING This product is not for human or veterinary use.
