Critical Role of Leucine-Valine Change in Distinct Low pH Requirements for Membrane Fusion between Two Related Retrovirus Envelopes

Côté, Marceline; Zheng, Yi; Li, Kun; Xiang, Shi Hua; Albritton, Lorraine M.; Liu, Shan-Lu

doi:10.1074/jbc.m111.334722

Cited by 12 publications

(15 citation statements)

References 53 publications

(37 reference statements)

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“…We performed metabolic labeling of 293T cells co-expressing IFITMs and JSRV Env, and determined shedding of JSRV SU in the presence or absence of a soluble form of Hyal2 (sHyal2). In our previous studies, we had established that shedding of JSRV SU into culture media is an important indicator of Hyal2 receptor-mediated triggering for the fusion activation of JSRV Env [28], [29], [30]. Here we observed that the levels of JSRV SU harvested from the culture media of 293T cells expressing IFITM1, 2 or 3 were comparable to those of parental cells, and that they all increased with the presence of sHyal2 in a dose-dependent manner (Fig.…”

Section: Resultssupporting

confidence: 58%

“…We chose the Jaagsiekte sheep retrovirus (JSRV) envelope (Env) and IAV hemagglutinin (HA) proteins as the model system of study because of some of their advantages. JSRV is a simple retrovirus, with Env-mediated membrane fusion and entry requiring both receptor-binding and low pH; an initial receptor binding primes the subsequent low pH-dependent conformational changes required for full activation [27], [28], [29], [30]. This unconventional two-step triggering mechanism was originally discovered in the avian sarcoma leukosis virus (ASLV) [31], and has now been suggested to operate in other enveloped viruses, including HCV [32].…”

Section: Introductionmentioning

confidence: 99%

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IFITM Proteins Restrict Viral Membrane Hemifusion

et al. 2013

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The interferon-inducible transmembrane (IFITM) protein family represents a new class of cellular restriction factors that block early stages of viral replication; the underlying mechanism is currently not known. Here we provide evidence that IFITM proteins restrict membrane fusion induced by representatives of all three classes of viral membrane fusion proteins. IFITM1 profoundly suppressed syncytia formation and cell-cell fusion induced by almost all viral fusion proteins examined; IFITM2 and IFITM3 also strongly inhibited their fusion, with efficiency somewhat dependent on cell types. Furthermore, treatment of cells with IFN also markedly inhibited viral membrane fusion and entry. By using the Jaagsiekte sheep retrovirus envelope and influenza A virus hemagglutinin as models for study, we showed that IFITM-mediated restriction on membrane fusion is not at the steps of receptor- and/or low pH-mediated triggering; instead, the creation of hemifusion was essentially blocked by IFITMs. Chlorpromazine (CPZ), a chemical known to promote the transition from hemifusion to full fusion, was unable to rescue the IFITM-mediated restriction on fusion. In contrast, oleic acid (OA), a lipid analog that generates negative spontaneous curvature and thereby promotes hemifusion, virtually overcame the restriction. To explore the possible effect of IFITM proteins on membrane molecular order and fluidity, we performed fluorescence labeling with Laurdan, in conjunction with two-photon laser scanning and fluorescence-lifetime imaging microscopy (FLIM). We observed that the generalized polarizations (GPs) and fluorescence lifetimes of cell membranes expressing IFITM proteins were greatly enhanced, indicating higher molecularly ordered and less fluidized membranes. Collectively, our data demonstrated that IFITM proteins suppress viral membrane fusion before the creation of hemifusion, and suggested that they may do so by reducing membrane fluidity and conferring a positive spontaneous curvature in the outer leaflets of cell membranes. Our study provides novel insight into the understanding of how IFITM protein family restricts viral membrane fusion and infection.

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Section: Resultssupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

IFITM Proteins Restrict Viral Membrane Hemifusion

et al. 2013

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“…Pseudovirion Production and Infection-GFP-encoding and alkaline phosphatase-encoding Moloney murine leukemia virus pseudovirions were produced as described previously (11,33). Lentiviral shRNA/AP-3 pseudotypes were generated according to the manufacturer's instructions (Sigma).…”

Section: Methodsmentioning

confidence: 99%

A Sorting Signal Suppresses IFITM1 Restriction of Viral Entry

Jia

et al. 2015

Journal of Biological Chemistry

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“…The experiments were performed as described (53,54). Briefly, 293T cells were transfected with plasmids encoding HIV-1 proviral DNAs or HIV-1 Gag, along with plasmids expressing TIMs or PS receptors.…”

Section: Methodsmentioning

confidence: 99%

TIM-family proteins inhibit HIV-1 release

Ablan

Miao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance TIM-family proteins have been recently shown to promote viral entry into host cells. Unexpectedly, we discovered that human TIM-1, along with TIM-3 and TIM-4, potently inhibits HIV-1 release. We showed that TIM-1 is incorporated into HIV-1 virions and retains HIV-1 particles on the plasma membrane via phosphatidylserine (PS), a phospholipid that is exposed on the cellular plasma membrane and the viral envelope. Expression of TIM-1 inhibits HIV-1 replication in CD4 + T cells, and knockdown of TIM-3 in monocyte-derived macrophages enhances HIV-1 production. We extended this function of TIMs to other PS receptors, and demonstrated that they also inhibited release of additional viruses, including murine leukemia virus and Ebola virus. The novel role of TIMs in blocking viral release provides new insights into viral replication and AIDS pathogenesis.

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Critical Role of Leucine-Valine Change in Distinct Low pH Requirements for Membrane Fusion between Two Related Retrovirus Envelopes

Cited by 12 publications

References 53 publications

IFITM Proteins Restrict Viral Membrane Hemifusion

IFITM Proteins Restrict Viral Membrane Hemifusion

A Sorting Signal Suppresses IFITM1 Restriction of Viral Entry

TIM-family proteins inhibit HIV-1 release

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