Viral subversion of selective autophagy is critical for biogenesis of virus replication organelles

Yun Lan, Sophie Wilhelmina Leur, Julia Ayano Fernando, Ho Him Wong, Martin Kampmann, Lewis Siu, Jingshu Zhang, Mingyuan Li, John M. Nicholls and Sumana Sanyal ()
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Yun Lan: University of Hong Kong
Sophie Wilhelmina Leur: University of Oxford
Julia Ayano Fernando: University of Hong Kong
Ho Him Wong: University of Hong Kong
Martin Kampmann: University of Hong Kong
Lewis Siu: University of Hong Kong
Jingshu Zhang: University of Hong Kong
Mingyuan Li: University of Hong Kong
John M. Nicholls: University of Hong Kong
Sumana Sanyal: University of Hong Kong

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Infection by many (+)RNA viruses is accompanied by ER-expansion and membrane remodelling to form viral replication organelles, followed by assembly and secretion of viral progenies. We previously identified that virus-triggered lipophagy was critical for flaviviral assembly, and is driven by the lipid droplet associated protein Ancient ubiquitin protein 1 (Aup1). A ubiquitin conjugating protein Ube2g2 that functions as a co-factor for Aup1 was identified as a host dependency factor in our study. Here we characterized its function: Ube2g2-deficient cells displayed a dramatic reduction in virus production, which could be rescued by reconstituting the wild-type but not the catalytically deficient (C89K) mutant of Ube2g2, suggesting that its enzymatic activity is necessary. Ube2g2 deficiency did not affect entry of virus particles but resulted in a profound loss in formation of replication organelles, and production of infectious progenies. This phenomenon resulted from its dual activity in (i) triggering lipophagy in conjunction with Aup1, and (ii) degradation of ER chaperones such as Herpud1, SEL1L, Hrd1, along with Sec62 to restrict ER-phagy upon Xbp1-IRE1 triggered ER expansion. Our results therefore underscore an exquisite fine-tuning of selective autophagy by flaviviruses that drive host membrane reorganization during infection to enable biogenesis of viral replication organelles.

Date: 2023
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DOI: 10.1038/s41467-023-38377-w

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