1887

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Volume 101, Issue 1

mTORC1 restricts hepatitis C virus RNA replication through ULK1-mediated suppression of miR-122 and facilitates post-replication events Free

Abstract

The mechanistic target of rapamycin (mTOR), an important kinase that assimilates several upstream signals, associates into two functional complexes, mTORC1 and mTORC2. In this study, we demonstrate that HCV infection activates mTORC1 that functions in important antiviral response. Pharmacological inhibition of mTOR complexes augmented cellular HCV RNA levels, the observation confirmed further by Raptor depletion, indicating antiviral roles of mTORC1. ULK1 depletion phenocopied mTOR inhibition and thus suggested that mTORC1 restricts HCV replication through ULK1. We reveal that ULK1 depletion augmented the levels of miR-122, a critical host factor for HCV replication, thus possibly regulating HCV replication. The increase in HCV RNA levels, however, failed to augment intracellular infectious virion production, reflecting a lower rate of virion assembly. Higher intracellular HCV RNA levels, however, did not result in a corresponding increase in HCV RNA and infectious titres in mTOR inhibited supernatants, but in contrast showed a consistent drop, confirming defective viral assembly caused by the inhibition. Consistent with this, the mTOR activator caused a significant drop in HCV RNA levels both in infected cells and in the supernatant. Our results demonstrate that ULK1 depletion did not affect autophagy, suggesting that ULK1-mediated HCV regulation is autophagy independent. Together, our data demonstrate that mTORC1 functions to suppress HCV RNA replication, but facilitates the virion packaging and release. Our studies reveal that the activation of mTOR by HCV infection is an antiviral measure by the cells.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): Autophagy , Hepatitis C virus , miR-122 , mTOR , Replication and ULK1
© 2020 The Authors
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2020-01-01
2024-04-25
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mTORC1 restricts hepatitis C virus RNA replication through ULK1-mediated suppression of miR-122 and facilitates post-replication events
J. Gen. Virol. 101, 86 (2020); https://doi.org/10.1099/jgv.0.001356
/content/journal/jgv/10.1099/jgv.0.001356
/content/journal/jgv/10.1099/jgv.0.001356
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