SARS-CoV-2 Diverges from Other Betacoronaviruses in Only Partially Activating the IRE1α/XBP1 Endoplasmic Reticulum Stress Pathway in Human Lung-Derived Cells
Long C. Nguyen, David M. Renner, Diane Silva, Dongbo Yang, Nicholas A. Parenti, Kaeri M. Medina, Vlad Nicolaescu, Haley Gula, Nir Drayman, Andrea Valdespino, Adil Mohamed, Christopher Dann, Kristin Wannemo, Lydia Robinson-Mailman, Alan Gonzalez, Letícia Stock, Mengrui Cao, Zeyu Qiao, Raymond E. Moellering, Savaş Tay, Glenn Randall, Michael F. Beers, Marsha Rich Rosner, Scott A. Oakes, Susan R. Weiss
Abstract
SARS-CoV-2 is the third lethal respiratory coronavirus, after MERS-CoV and SARS-CoV, to emerge this century, causing millions of deaths worldwide. Other common coronaviruses such as HCoV-OC43 cause less severe respiratory disease. Thus, it is imperative to understand the similarities and differences among these viruses in how each interacts with host cells. We focused here on the inositol-requiring enzyme 1α (IRE1α) pathway, part of the host unfolded protein response to virus-induced stress. We found that while MERS-CoV and HCoV-OC43 fully activate the IRE1α kinase and RNase activities, SARS-CoV-2 only partially activates IRE1α, promoting its kinase activity but not RNase activity. Based on IRE1α-dependent gene expression changes during infection, we propose that SARS-CoV-2 prevents IRE1α RNase activation as a strategy to limit detection by the host immune system.