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

Authors

• GL Shi
• S Ozog
• K Hermann
• BE Torbett
• AA Compton

Abstract

mTOR is the central regulator of cell growth, proliferation, and other anabolic processes required for cellular homeostasis. Rapamycin and other specific inhibitors of mTOR are considered promising anti-tumorigenic agents in cancer settings, which are also found to promote cellular transduction using lentiviral vectors. However, the precise mechanism was unknown. Here we report that mTOR inhibitor treatment results in a transient downregulation of the interferon-induced transmembrane (IFITM) proteins. IFITM proteins, especially IFITM3, are broadly active against a range of human pathogenic viruses. We found that the effect of rapamycin treatment on lentiviral transduction is diminished upon IFITM silencing or knockout in primary and transformed human cells, and the extent of transduction enhancement depends on basal expression of IFITM proteins, with a major contribution from IFITM3. The effect of acute rapamycin treatment on IFITM3 manifests at the level of protein, but not mRNA, and is selective. Rapamycin treatment leads to IFITM3 degradation, a process that requires endosomal trafficking, ubiquitination, and lysosomal acidification. However, the degradative process occurs independently of the autophagosome. Instead, we provide evidence that turnover requires TSG101, suggesting that IFITM3 is sorted into multivesicular bodies (MVB) prior to disposal in lysosomes. We also show that mTOR inhibition 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 of mTOR inhibitors enhancing virus entry into human cells and reveal a previously unrecognized immunosuppressive feature of these clinically important drugs that may impact antiviral immunity in vivo.

Scientific Focus Area: Virology

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