PMID- 30301809
OWN - NLM
STAT- MEDLINE
DCOM- 20181211
LR  - 20211204
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 115
IP  - 43
DP  - 2018 Oct 23
TI  - mTOR inhibitors lower an intrinsic barrier to virus infection mediated by IFITM3.
PG  - E10069-E10078
LID - 10.1073/pnas.1811892115 [doi]
AB  - Rapamycin and its derivatives are specific inhibitors of mammalian target of 
      rapamycin (mTOR) kinase and, as a result, are well-established immunosuppressants 
      and antitumorigenic agents. Additionally, this class of drug promotes gene 
      delivery by facilitating lentiviral vector entry into cells, revealing its 
      potential to improve gene therapy efforts. However, the precise mechanism was 
      unknown. Here, we report that mTOR inhibitor treatment results in down-regulation 
      of the IFN-induced transmembrane (IFITM) proteins. IFITM proteins, especially 
      IFITM3, are potent inhibitors of virus-cell fusion and are broadly active against 
      a range of pathogenic viruses. We found that the effect of rapamycin treatment on 
      lentiviral transduction is diminished upon IFITM silencing or knockout in primary 
      and transformed cells, and the extent of transduction enhancement depends on 
      basal expression of IFITM proteins, with a major contribution from IFITM3. The 
      effect of rapamycin treatment on IFITM3 manifests at the level of protein, but 
      not mRNA, and is selective, as many other endosome-associated transmembrane 
      proteins are unaffected. Rapamycin-mediated degradation of IFITM3 requires 
      endosomal trafficking, ubiquitination, endosomal sorting complex required for 
      transport (ESCRT) machinery, and lysosomal acidification. Since IFITM proteins 
      exhibit broad antiviral activity, we show that mTOR inhibition also promotes 
      infection by another IFITM-sensitive virus, Influenza A virus, but not infection 
      by Sendai virus, which is IFITM-resistant. Our results identify the molecular 
      basis by which mTOR inhibitors enhance virus entry into cells and reveal a 
      previously unrecognized immunosuppressive feature of these clinically important 
      drugs. In addition, this study uncovers a functional convergence between the mTOR 
      pathway and IFITM proteins at endolysosomal membranes.
CI  - Copyright (c) 2018 the Author(s). Published by PNAS.
FAU - Shi, Guoli
AU  - Shi G
AD  - HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer 
      Institute, Frederick, MD 21702.
FAU - Ozog, Stosh
AU  - Ozog S
AD  - Department of Immunology and Microbiology, The Scripps Research Institute, La 
      Jolla, CA 92037.
FAU - Torbett, Bruce E
AU  - Torbett BE
AD  - Department of Immunology and Microbiology, The Scripps Research Institute, La 
      Jolla, CA 92037.
FAU - Compton, Alex A
AU  - Compton AA
AUID- ORCID: 0000-0002-7508-4953
AD  - HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer 
      Institute, Frederick, MD 21702; alex.compton@nih.gov.
LA  - eng
GR  - F30 HL137563/HL/NHLBI NIH HHS/United States
GR  - P30 AI036214/AI/NIAID NIH HHS/United States
GR  - T32 GM007198/GM/NIGMS NIH HHS/United States
GR  - U54 GM103368/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20181009
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antiviral Agents)
RN  - 0 (IFITM3 protein, human)
RN  - 0 (Membrane Proteins)
RN  - 0 (RNA-Binding Proteins)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antiviral Agents/*pharmacology
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Endosomes/drug effects/metabolism/virology
MH  - HEK293 Cells
MH  - HeLa Cells
MH  - Host-Pathogen Interactions/drug effects
MH  - Humans
MH  - Membrane Proteins/*metabolism
MH  - Protein Transport/drug effects
MH  - RNA-Binding Proteins/*metabolism
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Virus Diseases/*drug therapy/*metabolism/virology
MH  - Virus Internalization/*drug effects
PMC - PMC6205447
OTO - NOTNLM
OT  - IFITM
OT  - endosome
OT  - fusion
OT  - interferon
OT  - virus
COIS- The authors declare no conflict of interest.
EDAT- 2018/10/12 06:00
MHDA- 2018/12/12 06:00
PMCR- 2018/10/09
CRDT- 2018/10/11 06:00
PHST- 2018/10/12 06:00 [pubmed]
PHST- 2018/12/12 06:00 [medline]
PHST- 2018/10/11 06:00 [entrez]
PHST- 2018/10/09 00:00 [pmc-release]
AID - 1811892115 [pii]
AID - 201811892 [pii]
AID - 10.1073/pnas.1811892115 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):E10069-E10078. doi: 
      10.1073/pnas.1811892115. Epub 2018 Oct 9.