Contribution of autophagy machinery factors to HCV and SARS-CoV-2 replication organelle formation

• Published in: Cell reports (Cambridge) Vol. 37; no. 8; p. 110049
• Main Authors: Twu, Woan-Ing, Lee, Ji-Young, Kim, Heeyoung, Prasad, Vibhu, Cerikan, Berati, Haselmann, Uta, Tabata, Keisuke, Bartenschlager, Ralf
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.11.2021; Cell Press
• Subjects: Autophagosomes - metabolism; autophagy; Autophagy - physiology; Beclin 1; Carrier Proteins - metabolism; Class III Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Class III Phosphatidylinositol 3-Kinases - metabolism; class III PI3K; coronavirus; daclatasvir; DFCP1; DMV; Hepacivirus - physiology; hepatitis C virus; Humans; Phosphatidylinositol Phosphates - metabolism; PI3P; replication organelle; RNA, Viral - biosynthesis; SARS-CoV-2 - physiology; Viral Nonstructural Proteins - metabolism; Viral Replication Compartments - metabolism; Virus Replication; autophagy; PI3P; Beclin 1; hepatitis C virus; coronavirus; class III PI3K; DMV; DFCP1; replication organelle; daclatasvir
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.110049

Positive-strand RNA viruses replicate in close association with rearranged intracellular membranes. For hepatitis C virus (HCV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), these rearrangements comprise endoplasmic reticulum (ER)-derived double membrane vesicles (DMVs) serving as RNA replication sites. Cellular factors involved in DMV biogenesis are poorly defined. Here, we show that despite structural similarity of viral DMVs with autophagosomes, conventional macroautophagy is dispensable for HCV and SARS-CoV-2 replication. However, both viruses exploit factors involved in autophagosome formation, most notably class III phosphatidylinositol 3-kinase (PI3K). As revealed with a biosensor, PI3K is activated in cells infected with either virus to produce phosphatidylinositol 3-phosphate (PI3P) while kinase complex inhibition or depletion profoundly reduces replication and viral DMV formation. The PI3P-binding protein DFCP1, recruited to omegasomes in early steps of autophagosome formation, participates in replication and DMV formation of both viruses. These results indicate that phylogenetically unrelated HCV and SARS-CoV-2 exploit similar components of the autophagy machinery to create their replication organelles. [Display omitted] •Conventional macroautophagy is dispensable for HCV and SARS-CoV-2 replication•Components of the class III PI3K complex promote HCV and SARS-CoV-2 replication•Class III PI3K and DFCP1 contribute to membranous replication organelle formation Twu et al. investigate involvement of autophagy machinery components in HCV and SARS-CoV-2 replication. Conventional macroautophagy is dispensable for replication of either virus. However, factors involved in autophagosome biogenesis, including components of the class III PI3K complex, contribute to viral replication. Most likely they promote membranous replication organelle formation.