PMID:28389568

Citation	Hansen, MD, Johnsen, IB, Stiberg, KA, Sherstova, T, Wakita, T, Richard, GM, Kandasamy, RK, Meurs, EF and Anthonsen, MW (2017) Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M. Proc. Natl. Acad. Sci. U.S.A. 114:E3462-E3471
Abstract	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.
Links	PubMed PMC5410803 Online version:10.1073/pnas.1616683114
Keywords	Autophagy; Autophagy-Related Protein-1 Homolog/genetics; Autophagy-Related Protein-1 Homolog/metabolism; Cell Line, Tumor; GTP-Binding Proteins/genetics; GTP-Binding Proteins/metabolism; Golgi Apparatus/genetics; Golgi Apparatus/metabolism; Golgi Apparatus/virology; Guanine Nucleotide Exchange Factors/genetics; Guanine Nucleotide Exchange Factors/metabolism; Hepacivirus/physiology; Humans; Intracellular Membranes/metabolism; Intracellular Membranes/virology; Intracellular Signaling Peptides and Proteins/genetics; Intracellular Signaling Peptides and Proteins/metabolism; Phosphorylation/genetics; Virus Replication/physiology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:IRGM	involved_in	GO:0001934: positive regulation of protein phosphorylation	ECO:0000315: mutant phenotype evidence used in manual assertion		P	happens_during:(GO:0098586) has_input:(UniProtKB:Q92538)	Seeded From UniProt	complete
HUMAN:IRGM	located_in	GO:0000139: Golgi membrane	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:IRGM	located_in	GO:0005739: mitochondrion	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:IRGM	located_in	GO:0005794: Golgi apparatus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:IRGM	involved_in	GO:0061739: protein lipidation involved in autophagosome assembly	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:IRGM	involved_in	GO:0075044: positive regulation by symbiont of host autophagy	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:IRGM	involved_in	GO:0071902: positive regulation of protein serine/threonine kinase activity	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:IRGM	enables	GO:0043539: protein serine/threonine kinase activator activity	ECO:0000315: mutant phenotype evidence used in manual assertion		F	part_of:(GO:0098586) has_input:(UniProtKB:O75385)	Seeded From UniProt	complete
HUMAN:IRGM	involved_in	GO:0098586: cellular response to virus	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:ULK1	involved_in	GO:0075044: positive regulation by symbiont of host autophagy	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:Q8IYT8	P		Seeded From UniProt	complete
HUMAN:ARF1	involved_in	GO:0098586: cellular response to virus	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:ULK2	involved_in	GO:0075044: positive regulation by symbiont of host autophagy	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:O75385	P		Seeded From UniProt	complete
HUMAN:GBF1	involved_in	GO:0098586: cellular response to virus	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:ATG5	involved_in	GO:0075044: positive regulation by symbiont of host autophagy	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:O95352	P		Seeded From UniProt	complete
HUMAN:ATG7	involved_in	GO:0075044: positive regulation by symbiont of host autophagy	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:Q9H1Y0	P		Seeded From UniProt	complete

References

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