HCV-induced autophagosomes are generated via homotypic fusion of phagophores that mediate HCV RNA replication.
HCV-induced autophagosomes are generated via homotypic fusion of phagophores that mediate HCV RNA replication.
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DOI：
10.1371/journal.ppat.1006609
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发表时间：
2017-09
期刊：
影响因子：
6.7
通讯作者：
Ou JJ
中科院分区：
文献类型：
--
作者：
Wang L;Kim JY;Liu HM;Lai MMC;Ou JJ
Hepatitis C virus (HCV) induces autophagy to promote its replication, including its RNA replication, which can take place on double-membrane vesicles known as autophagosomes. However, how HCV induces the biogenesis of autophagosomes and how HCV RNA replication complex may be assembled on autophagosomes were largely unknown. During autophagy, crescent membrane structures known as phagophores first appear in the cytoplasm, which then progress to become autophagosomes. By conducting electron microscopy and in vitro membrane fusion assay, we found that phagophores induced by HCV underwent homotypic fusion to generate autophagosomes in a process dependent on the SNARE protein syntaxin 7 (STX7). Further analyses by live-cell imaging and fluorescence microscopy indicated that HCV-induced phagophores originated from the endoplasmic reticulum (ER). Interestingly, comparing with autophagy induced by nutrient starvation, the progression of phagophores to autophagosomes induced by HCV took significantly longer time, indicating fundamental differences in the biogenesis of autophagosomes induced by these two different stimuli. As the knockdown of STX7 to inhibit the formation of autophagosomes did not affect HCV RNA replication, and purified phagophores could mediate HCV RNA replication, the assembly of the HCV RNA replication complex on autophagosomes apparently took place during the formative stage of phagophores. These findings provided important information for understanding how HCV controlled and modified this important cellular pathway for its own replication. Autophagy is a catabolic process that is important for maintaining cellular homeostasis. During autophagy, crescent membrane structures known as phagophores first appear in the cytoplasm, which then expand to form enclosed double-membrane vesicles known as autophagosomes. It has been shown that hepatitis C virus (HCV) induces autophagy and uses autophagosomal membranes for its RNA replication. In this report, we studied the biogenesis pathway of HCV-induced autophagosomes and demonstrated that phagophores induced by HCV originated from the endoplasmic reticulum and undergo homotypic fusion to generate autophagosomes, and that the HCV RNA replication complex is assembled on phagophores prior to the formation of autophagosomes. These findings provided important information for understanding how an RNA virus controls this important cellular pathway for its replication.
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