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PMID:28389568

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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

Significance

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

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

Notes

See also

References

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