PMID- 31821132
OWN - NLM
STAT- MEDLINE
DCOM- 20200805
LR  - 20211204
IS  - 1465-2099 (Electronic)
IS  - 0022-1317 (Linking)
VI  - 101
IP  - 1
DP  - 2020 Jan
TI  - mTORC1 restricts hepatitis C virus RNA replication through ULK1-mediated 
      suppression of miR-122 and facilitates post-replication events.
PG  - 86-95
LID - 10.1099/jgv.0.001356 [doi]
AB  - 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.
FAU - Johri, Manish Kumar
AU  - Johri MK
AD  - Academy of Scientific and Innovative Research (AcSIR), CSIR-CCMB Campus, 
      Hyderabad, India.
AD  - CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad-500007, 
      India.
FAU - Lashkari, Hiren Vasantrai
AU  - Lashkari HV
AD  - CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad-500007, 
      India.
FAU - Gupta, Divya
AU  - Gupta D
AD  - CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad-500007, 
      India.
FAU - Vedagiri, Dhiviya
AU  - Vedagiri D
AD  - Academy of Scientific and Innovative Research (AcSIR), CSIR-CCMB Campus, 
      Hyderabad, India.
AD  - CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad-500007, 
      India.
FAU - Harshan, Krishnan Harinivas
AU  - Harshan KH
AD  - CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad-500007, 
      India.
AD  - Academy of Scientific and Innovative Research (AcSIR), CSIR-CCMB Campus, 
      Hyderabad, India.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Gen Virol
JT  - The Journal of general virology
JID - 0077340
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (MIRN122 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Autophagy-Related Protein-1 Homolog)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (ULK1 protein, human)
SB  - IM
MH  - Autophagy/genetics
MH  - Autophagy-Related Protein-1 Homolog/*genetics
MH  - Cell Line, Tumor
MH  - Hepacivirus/*genetics
MH  - Hepatitis C/*genetics/virology
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/*genetics
MH  - MicroRNAs/*genetics
MH  - Signal Transduction/genetics
MH  - TOR Serine-Threonine Kinases/*genetics
MH  - Virus Replication/*genetics
OTO - NOTNLM
OT  - Autophagy
OT  - Hepatitis C virus
OT  - Replication
OT  - ULK1
OT  - mTOR
OT  - miR-122
EDAT- 2019/12/11 06:00
MHDA- 2020/08/06 06:00
CRDT- 2019/12/11 06:00
PHST- 2019/12/11 06:00 [pubmed]
PHST- 2020/08/06 06:00 [medline]
PHST- 2019/12/11 06:00 [entrez]
AID - 10.1099/jgv.0.001356 [doi]
PST - ppublish
SO  - J Gen Virol. 2020 Jan;101(1):86-95. doi: 10.1099/jgv.0.001356.