About: mTOR inhibitors lower an intrinsic barrier to virus infection mediated by IFITM3

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An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	mTOR inhibitors lower an intrinsic barrier to virus infection mediated by IFITM3
Creator	Shi, Guoli Ozog, Stosh Compton, Alex Torbett, Bruce
Source	Medline; PMC
abstract	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.
has issue date	2018-10-23(xsd:dateTime)
bibo:doi	10.1073/pnas.1811892115
bibo:pmid	30301809
has license	cc-by-nc-nd
sha1sum (hex)	37feea85864da899f6c9b22a7d89c8598fa38a29
schema:url	https://doi.org/10.1073/pnas.1811892115
resource representing a document's title	mTOR inhibitors lower an intrinsic barrier to virus infection mediated by IFITM3
has PubMed Central identifier	PMC6205447
has PubMed identifier	30301809
schema:publication	Proc Natl Acad Sci U S A
resource representing a document's body	covid:37feea85864da899f6c9b22a7d89c8598fa38a29#body_text
is schema:about of	named entity 'LOWER' named entity 'MEMBRANES' named entity 'RAPAMYCIN' named entity 'ENTRY' named entity 'TRANSDUCTION' named entity 'VIRUSES' named entity 'ITS' named entity 'PATHWAY' named entity 'PRECISE' named entity 'EFFECT' named entity 'FOUND' named entity 'EXHIBIT' named entity 'PROTEINS' named entity 'BROAD' named entity 'DIMINISHED' named entity 'IMMUNOSUPPRESSANTS' named entity 'FUSION' named entity 'ENDOSOME' named entity 'ENHANCE' named entity 'CELLS' named entity 'MTOR INHIBITOR' named entity 'CONVERGENCE' named entity 'SENSITIVE' named entity 'IDENTIFY' named entity 'ACIDIFICATION' named entity 'TRANSMEMBRANE PROTEINS' named entity 'POTENTIAL' named entity 'DRUG' named entity 'SELECTIVE' named entity 'INHIBITION' named entity 'RESISTANT' named entity 'DRUGS' named entity 'reveal' named entity 'Sendai' named entity 'lysosomal' named entity 'specific' named entity 'identify' named entity 'inhibitors' named entity 'proteins' named entity 'inhibitors' named entity 'IFITM3' named entity 'PRIMARY' named entity 'MACHINERY' named entity 'ENDOSOMAL SORTING COMPLEX REQUIRED FOR TRANSPORT' named entity 'MOLECULAR BASIS' named entity 'DEGRADATION' named entity 'MTOR INHIBITORS' named entity 'LENTIVIRAL VECTOR' named entity 'MANIFESTS' named entity 'OUR' named entity 'VIRUS' named entity 'MEDIATED' named entity 'ACTIVE' named entity 'TRANSFORMED' named entity 'ENHANCEMENT' named entity 'INHIBITORS' named entity 'REVEALING' named entity 'LEVEL' named entity 'IFN' named entity 'PROTEIN' named entity 'BARRIER' named entity 'INTRINSIC' named entity 'MEDIATED' named entity 'MTOR INHIBITORS' named entity 'LYSOSOMAL' named entity 'CONTRIBUTION' named entity 'CELL FUSION' named entity 'BASAL' named entity 'UNRECOGNIZED' named entity 'RAPAMYCIN TREATMENT' named entity 'UNAFFECTED' named entity 'IFITM3' named entity 'INFLUENZA A VIRUS' named entity 'ASSOCIATED' named entity 'SENDAI VIRUS' named entity 'BUT' named entity 'THESE' named entity 'PATHOGENIC'

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