PMID:23358889

Citation	Li, K, Markosyan, RM, Zheng, YM, Golfetto, O, Bungart, B, Li, M, Ding, S, He, Y, Liang, C, Lee, JC, Gratton, E, Cohen, FS and Liu, SL (2013) IFITM Proteins Restrict Viral Membrane Hemifusion. PLoS Pathog. 9:e1003124
Abstract	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.
Links	PubMed PMC3554583 Online version:10.1371/journal.ppat.1003124
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:IFM1		GO:0046597: regulation of defense response to virus by host	ECO:0000314:		P		Figues 1, particularly B, and 3 indicate that IFITM1 protein acts as a defense mechanism against viral membrane fusion.	complete CACAO 6529
HUMAN:IFM1		GO:0046597: negative regulation of viral entry into host cell	ECO:0000314:		P		Figure 1 IFITM proteins differentially restrict JSRV, 10A1 MLV, IAV and VSV entry and Figure 4 Cell-cell fusion induced by JSRV Env is inhibited by IFITM proteins, and extracellular low pH pulse cannot overcome IFITM1-mediated restriction on JSRV entry clearly show that IFITM1 is acting as a defense by redistricting the virus from entering the host.	complete CACAO 6575
HUMAN:IFM1	involved_in	GO:0046597: negative regulation of viral entry into host cell	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:IFM2		GO:0046597: negative regulation of viral entry into host cell	ECO:0000314:		P		Figues 1, particularly B, and 3 indicate that IFITM2 protein acts as a defense mechanism against viral membrane fusion.	complete CACAO 6532
HUMAN:IFM2	involved_in	GO:0046597: negative regulation of viral entry into host cell	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:IFM3		GO:0046597: negative regulation of viral entry into host cell	ECO:0000315:		P		Figues 1, particularly B, and 3 indicate that IFITM3 protein acts as a defense mechanism against viral membrane fusion.	complete CACAO 6534
HUMAN:IFM3	involved_in	GO:0046597: negative regulation of viral entry into host cell	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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