Endoplasmic Reticulum Stress and Differential Regulation of UPR-Specific Genes in Response to SARS-CoV-2 Infection

The coronavirus spike (S) protein is folded within the lumen of the endoplasmic reticulum (ER) and can induce ER stress and the unfolded protein response (UPR). Although SARS-CoV-2 infection is known to trigger ER stress, it remains unclear how UPR-associated genes respond across different levels of viral replication. To address this question, I quantified SARS-CoV-2 subgenomic RNAs (sgRNAs) and the expression of fourteen UPR-associated genes in A549 cells, A549 cells expressing human ACE2 (A549+hACE2), and Calu-3 cells infected with SARS-CoV-2. These genes represent the three branches of mammalian UPR. Cells with limited viral gene expression exhibited transcriptional changes consistent with adaptive UPR activation, including increased expression of genes associated with the IRE1α-XBP1 pathway and ER protein-folding functions. In contrast, cells expressing abundant viral sgRNAs displayed strong induction of the PERK-associated genes ATF4 and DDIT3, together with reduced expression of several ER chaperone genes, including HSPA5, CALR, CANX, and HSP90B1. Calu-3 cells exhibited an intermediate response. These findings reveal a continuum of ER-stress responses across increasing levels of SARS-CoV-2 infection and suggest that productive viral replication is associated with selective remodeling of the UPR transcriptional program rather than uniform activation of all UPR pathways. The results shed light on the conflict between the virus and the host cell in controlling the cell fate upon viral infection.