SARS-CoV-2 ORF3A interacts with the Clic-like chloride channel-1 (CLCC1) and triggers an unfolded protein response [PeerJ]

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 CLCC1. ORF3A expression in 293T cells induced cell death and this was rescued by the chemical chaperone taurodeoxycholic acid (TUDCA). Cells with CLCC1 knockdown were partially protected from ORF3A-mediated cell death. CLCC1 knockdown upregulated several of the homeostatic UPR targets induced by ORF3A expression, including HSPA6 and spliced XBP1, and these were not further upregulated by ORF3A. Our data suggest a model where CLCC1 silencing triggers a homeostatic UPR that prevents cell death due to ORF3A expression.

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RNA-Guided Human Genome Engineering via Cas9

Gregory Ku UCSF Health

SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases - ScienceDirect

SARS-CoV-2 ORF3A interacts with the Clic-like chloride channel-1 (CLCC1) and triggers an unfolded protein response [PeerJ]

Pathogens, Free Full-Text

Frontiers Understanding the Role of SARS-CoV-2 ORF3a in Viral Pathogenesis and COVID-19

Publications

Detecting SARS-CoV-2 Orf3a and E ion channel activity in COVID-19 blood samples, Journal of Clinical and Translational Science

Frontiers Structural Analysis of SARS-CoV-2 ORF8 Protein: Pathogenic and Therapeutic Implications

Frontiers The Role of Unfolded Protein Response in Coronavirus Infection and Its Implications for Drug Design

Frontiers SARS-CoV-2 Accessory Proteins in Viral Pathogenesis: Knowns and Unknowns

The SARS-CoV-2 accessory protein Orf3a is not an ion channel, but does interact with trafficking proteins