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

• Published in: Nature communications Vol. 14; no. 1; p. 2698
• Main Authors: Lan, Yun, van Leur, Sophie Wilhelmina, Fernando, Julia Ayano, Wong, Ho Him, Kampmann, Martin, Siu, Lewis, Zhang, Jingshu, Li, Mingyuan, Nicholls, John M., Sanyal, Sumana
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10-05-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 14/1; 14/19; 38; 38/89; 631/80/642/1463; 692/420/254; 692/699/255/2514; 82/80; Assembly; Autophagy; Autophagy - genetics; Biosynthesis; Enzymatic activity; Flavivirus - metabolism; Humanities and Social Sciences; Lipid Droplets - metabolism; Lipids; Membranes; multidisciplinary; Organelles; Proteins; Proteins - metabolism; Replication; RNA viruses; Science; Science (multidisciplinary); Ubiquitin; Ubiquitin-conjugating enzyme; Ubiquitins - metabolism; Virus Replication - genetics; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-38377-w

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.
Virus triggered lipophagy is important for flaviviral assembly and coordinated by Aup1 and the ubiquitin conjugating enzyme E2. Here, Lan
et al
further characterise the interplay between these proteins and how they function to modulate selective autophagy and viral replication.