SARS-CoV-2 interacts with the Clic-like chloride channel-1 () and triggers an unfolded protein response.

Understanding the interactions between SARS-CoV-2 and host cell machinery may reveal new targets to treat COVID-19. We focused on an interaction between the SARS-CoV-2 ORF3A accessory protein and the CLIC-like chloride channel-1 (CLCC1). We found that ORF3A partially co-localized with CLCC1 and that ORF3A and CLCC1 could be co-immunoprecipitated. Since CLCC1 plays a role in the unfolded protein response (UPR), we hypothesized that ORF3A may also play a role in the UPR. Indeed, ORF3A expression triggered a transcriptional UPR that was similar to knockdown of . ORF3A expression in 293T cells induced cell death and this was rescued by the chemical chaperone taurodeoxycholic acid (TUDCA). Cells with knockdown were partially protected from ORF3A-mediated cell death. knockdown upregulated several of the homeostatic UPR targets induced by ORF3A expression, including and spliced and these were not further upregulated by ORF3A. Our data suggest a model where silencing triggers a homeostatic UPR that prevents cell death due to ORF3A expression.