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福利彩快乐十分怎么玩:TIM-mediated inhibition of HIV-1 release is antagonized by Nef but potentiated by SERINC proteins
广东快乐十分投注下载 www.hmclip.net Edited by Michael Emerman, Fred Hutchinson Cancer Research Center, Seattle, WA, and accepted by Editorial Board Member Stephen P. Goff February 3, 2019 (received for review November 15, 2018)
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TIM proteins inhibit release of HIV-1 and other enveloped viruses. However, it is currently unknown whether and how the virus counteracts this restriction. In this work, we demonstrate that Nef proteins of HIV-1 and other lentiviruses function as antagonists to overcome the TIM-mediated restriction. TIM-1 is more potent at inhibiting release of Nef-deficient HIV-1 relative to wild-type (WT) HIV-1, and ectopic expression of Nef relieves this restriction. Interestingly, we find that SERINC proteins potentiate TIM-mediated inhibition of HIV-1 release likely by stabilizing TIM-1 expression. Our work reveals a role for lentiviral Nef in antagonizing TIMs, in part through SERINCs.
The T cell Ig and mucin domain (TIM) proteins inhibit release of HIV-1 and other enveloped viruses by interacting with cell- and virion-associated phosphatidylserine (PS). Here, we show that the Nef proteins of HIV-1 and other lentiviruses antagonize TIM-mediated restriction. TIM-1 more potently inhibits the release of Nef-deficient relative to Nef-expressing HIV-1, and ectopic expression of Nef relieves restriction. HIV-1 Nef does not down-regulate the overall level of TIM-1 expression, but promotes its internalization from the plasma membrane and sequesters its expression in intracellular compartments. Notably, Nef mutants defective in modulating membrane protein endocytic trafficking are incapable of antagonizing TIM-mediated inhibition of HIV-1 release. Intriguingly, depletion of SERINC3 or SERINC5 proteins in human peripheral blood mononuclear cells (PBMCs) attenuates TIM-1 restriction of HIV-1 release, in particular that of Nef-deficient viruses. In contrast, coexpression of SERINC3 or SERINC5 increases the expression of TIM-1 on the plasma membrane and potentiates TIM-mediated inhibition of HIV-1 production. Pulse-chase metabolic labeling reveals that the half-life of TIM-1 is extended by SERINC5 from <2 to ～6 hours, suggesting that SERINC5 stabilizes the expression of TIM-1. Consistent with a role for SERINC protein in potentiating TIM-1 restriction, we find that MLV glycoGag and EIAV S2 proteins, which, like Nef, antagonize SERINC-mediated diminishment of HIV-1 infectivity, also effectively counteract TIM-mediated inhibition of HIV-1 release. Collectively, our work reveals a role of Nef in antagonizing TIM-1 and highlights the complex interplay between Nef and HIV-1 restriction by TIMs and SERINCs.
?1M.L., A.A.W., and J.Y. contributed equally to this work.
?2Present address: Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104.
?3Present address: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115.
- ?4To whom correspondence should be addressed. Email: .
Author contributions: M.L., A.A.W., J.Y., C.Z., H.-Y.C., Y.-M.Z., A.F., B.M.R., S.G., E.O.F., and S.-L.L. designed research; M.L., A.A.W., J.Y., C.Z., H.-Y.C., Y.-M.Z., A.F., and S.-L.L. performed research; E.O.F. contributed new reagents/analytic tools; M.L., A.A.W., J.Y., C.Z., H.-Y.C., Y.-M.Z., A.F., B.M.R., S.G., S.L., E.O.F., and S.-L.L. analyzed data; and M.L., A.A.W., J.Y., E.O.F., and S.-L.L. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. M.E. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1819475116/-/DCSupplemental.
Published under the PNAS license.