Publications

Proceedings of the National Academy of Sciences of the United States of America. 2021-09-07; 118.36:

Influenza A viruses balance ER stress with host protein synthesis shutoff

Mazel-Sanchez B, Iwaszkiewicz J, Bonifacio JPP, Silva F, Niu C, Strohmeier S, Eletto D, Krammer F, Tan G, Zoete V, Hale BG, Schmolke M

PMID: 34479996

Abstract

Excessive production of viral glycoproteins during infections poses a tremendous stress potential on the endoplasmic reticulum (ER) protein folding machinery of the host cell. The host cell balances this by providing more ER resident chaperones and reducing translation. For viruses, this unfolded protein response (UPR) offers the potential to fold more glycoproteins. We postulated that viruses could have developed means to limit the inevitable ER stress to a beneficial level for viral replication. Using a relevant human pathogen, influenza A virus (IAV), we first established the determinant for ER stress and UPR induction during infection. In contrast to a panel of previous reports, we identified neuraminidase to be the determinant for ER stress induction, and not hemagglutinin. IAV relieves ER stress by expression of its nonstructural protein 1 (NS1). NS1 interferes with the host messenger RNA processing factor CPSF30 and suppresses ER stress response factors, such as XBP1. In vivo viral replication is increased when NS1 antagonizes ER stress induction. Our results reveal how IAV optimizes glycoprotein expression by balancing folding capacity.

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