Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 17; pp. E3462 - E3471
• Main Authors: Hansen, Marianne D., Johnsen, Ingvild B., Stiberg, Kim A., Sherstova, Tatyana, Wakita, Takaji, Richard, Gabriel Mary, Kandasamy, Richard K., Meurs, Eliane F., Anthonsen, Marit W.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.04.2017
• Series: PNAS Plus
• Subjects: Autophagy; Biological Sciences; Cellular Biology; Fragmentation; Golgi apparatus; Guanine; Guanine nucleotide exchange factor; Guanosine triphosphatases; Hepatitis; Hepatitis C; Immunity; Infections; Intracellular; Life Sciences; Membranes; Microbiology and Parasitology; Phagocytosis; Phosphorylation; PNAS Plus; Replication; Ribonucleic acid; RNA; RNA viruses; Subcellular Processes; Virology; Viruses; HCV; autophagy; Golgi fragmentation; membranous web; IRGM
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1616683114

Positive-stranded RNA viruses, such as hepatitis C virus (HCV), assemble their viral replication complexes by remodeling host intracellular membranes to a membranous web. The precise composition of these replication complexes and the detailed mechanisms by which they are formed are incompletely understood. Here we show that the human immunity-related GTPase M (IRGM), known to contribute to autophagy, plays a previously unrecognized role in this process. We show that IRGM is localized at the Golgi apparatus and regulates the fragmentation of Golgi membranes in response to HCV infection, leading to colocalization of Golgi vesicles with replicating HCV. Our results show that IRGM controls phosphorylation of GBF1, a guanine nucleotide exchange factor for Arf-GTPases, which normally operates in Golgi membrane dynamics and vesicle coating in resting cells. We also find that HCV triggers IRGM-mediated phosphorylation of the early autophagy initiator ULK1, thereby providing mechanistic insight into the role of IRGM in HCV-mediated autophagy. Collectively, our results identify IRGM as a key Golgi-situated regulator that links intracellular membrane remodeling by autophagy and Golgi fragmentation with viral replication.