期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 17, 页码 E3462-E3471出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1616683114
关键词
HCV; Golgi fragmentation; autophagy; IRGM; membranous web
资金
- Liaison Committee
- Cancer Fund at St. Olav's Hospital
- Norwegian Cancer Society
- Research Council of Norway
- Research Council of Norway (CEMIR through Centres of Excellence Funding Scheme) [223255/F50]
- NTNU
- Institut Pasteur, Paris
- Grants-in-Aid for Scientific Research [17K09447] Funding Source: KAKEN
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.
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