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Prasad et al., 2023, Enhanced SARS-CoV-2 entry via UPR-dependent AMPK-related kinase NUAK2, TBA
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) induces remod-elling of the endoplasmic reticulum (ER) for the formation of its replication organelles, thereby causing ER stress and triggering an unfolded protein response (UPR). However, the contribution of individual UPR pathways to infection is poorly defined. Here, we found that SARS-CoV-2 infection causes marginal activation of the signalling sensor IRE1α leading to its phosphorylation, clustering in the form of dense ER membrane rear-rangements with embedded membrane openings, and XBP1 splicing. In search for fac-tors differentially regulated by IRE1α-XBP1 during SARS-CoV-2 infection, we identified stress-activated kinase NUAK2 as a novel host-dependency factor for SARS-CoV-2 and other coronaviruses (HCoV-229E and MERS-CoV) entry. Reducing NUAK2 abundance or kinase activity impaired SARS-CoV-2 particle binding and internalization by decreas-ing cell surface levels of viral receptors, and viral trafficking likely by modulating the ac-tin cytoskeleton. Our data suggest that SARS-CoV-2 triggered UPR induces NUAK2, promoting virion binding to cells by maintaining ACE2 cell surface levels and regulating virion trafficking, a principle that might be exploited by other coronaviruses.
Should you encounter any issues or have any questions please contact Vibhu Prasad vibhurprasad@gmail.com, Ralf Bartenschlager ralf.bartenschlager@med.uni-heidelberg.de or Michael Boutros m.boutros@dkfz.de.
Raw sequencing read data are deposit at ENA under the Study ID: PRJEB51271