Brass, A.L. et al. The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus. Cell 139, 1243-1254

Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard Medical School, Charlestown, MA 02129, USA.
Cell (Impact Factor: 32.24). 12/2009; 139(7):1243-54. DOI: 10.1016/j.cell.2009.12.017
Source: PubMed


Influenza viruses exploit host cell machinery to replicate, resulting in epidemics of respiratory illness. In turn, the host expresses antiviral restriction factors to defend against infection. To find host cell modifiers of influenza A H1N1 viral infection, we used a functional genomic screen and identified over 120 influenza A virus-dependency factors with roles in endosomal acidification, vesicular trafficking, mitochondrial metabolism, and RNA splicing. We discovered that the interferon-inducible transmembrane proteins IFITM1, 2, and 3 restrict an early step in influenza A viral replication. The IFITM proteins confer basal resistance to influenza A virus but are also inducible by interferons type I and II and are critical for interferon's virustatic actions. Further characterization revealed that the IFITM proteins inhibit the early replication of flaviviruses, including dengue virus and West Nile virus. Collectively this work identifies a family of antiviral restriction factors that mediate cellular innate immunity to at least three major human pathogens.

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Available from: Sinu P John, Apr 09, 2014
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    • "Virus restriction by individual IFITMs depends both on cell type and the intracellular location of each family member. For example, HIV, which undergoes viral envelope-cell membrane fusion at the cell surface or within early endosomes, is more restricted by IFITM1 (Lu et al., 2011), while influenza A virus, which requires pH-dependent changes in envelope glycoprotein conformation for viral fusion at late endosomes/lysosomes, is more restricted by IFITM2/3 (Brass et al., 2009; Desai et al., 2014; Feeley et al., 2011; John et al., 2013). IFITMs appear to block viral infection by reducing host membrane fluidity at sites of viral fusion through self-interactions and/or interactions with nearby transmembrane proteins, leading to inhibition of viral fusion pore formation and increased trafficking of trapped viruses to the lysosome for degradation (Desai et al., 2014; Lin et al., 2013). "
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    ABSTRACT: The interferon (IFN)-induced transmembrane (IFITM) proteins are critical mediators of the host antiviral response. Here, we expand the role of IFITM proteins to host defense against intracellular bacterial infection by demonstrating that they restrict Mycobacterium tuberculosis (MTb) intracellular growth. Simultaneous knockdown of IFITM1, IFITM2, and IFITM3 by RNAi significantly enhances MTb growth in human monocytic and alveolar/epithelial cells, whereas individual overexpression of each IFITM impairs MTb growth in these cell types. Furthermore, MTb infection, Toll-like receptor 2 and 4 ligands, and several proinflammatory cytokines induce IFITM1-3 gene expression in human myeloid cells. We find that IFITM3 co-localizes with early and, in particular, late MTb phagosomes, and overexpression of IFITM3 enhances endosomal acidification in MTb-infected monocytic cells. These findings provide evidence that the antiviral IFITMs participate in the restriction of mycobacterial growth, and they implicate IFITM-mediated endosomal maturation in its antimycobacterial activity.
    Full-text · Article · Nov 2015 · Cell Reports
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    • "Among these, APOBEC3G, TRIM5a, Tetherin or Bst2, SAMHD1, and MxB have been reported as potent anti-HIV restriction factors (Goujon et al., 2013; Hrecka et al., 2011; Kane et al., 2013; Laguette et al., 2011; Liu et al., 2013; Neil et al., 2008; Sadler and Williams, 2008; Sheehy et al., 2002; Stremlau et al., 2004; Van Damme et al., 2008). The interferon-induced transmembrane (IFITM) proteins are recently identified ISGs that have been shown to inhibit a number of viruses, including influenza A virus (IAV), West Nile virus, Dengue virus, Marburg virus (MARV), Ebola virus (EBOV), SARS coronavirus (SARS-CoV), vesicular stomatitis virus (VSV), and HIV type 1 (HIV-1) (Brass et al., 2009; Chutiwitoonchai et al., 2013; Huang et al., 2011; Jiang et al., 2010; Li et al., 2013; Lu et al., 2011; Schoggins et al., 2011; Weidner et al., 2010). However, the underlying mechanism by which IFITMs broadly inhibit viral infection is currently not well understood. "
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    ABSTRACT: The interferon-induced transmembrane (IFITM) proteins have been recently shown to restrict HIV-1 and other viruses. Here, we provide evidence that IFITM proteins, particularly IFITM2 and IFITM3, specifically antagonize the HIV-1 envelope glycoprotein (Env), thereby inhibiting viral infection. IFITM proteins interact with HIV-1 Env in viral producer cells, leading to impaired Env processing and virion incorporation. Notably, the level of IFITM incorporation into HIV-1 virions does not strictly correlate with the extent of inhibition. Prolonged passage of HIV-1 in IFITM-expressing T lymphocytes leads to emergence of Env mutants that overcome IFITM restriction. The ability of IFITMs to inhibit cell-to-cell infection can be extended to HIV-1 primary isolates, HIV-2 and SIVs; however, the extent of inhibition appears to be virus-strain dependent. Overall, our study uncovers a mechanism by which IFITM proteins specifically antagonize HIV-1 Env to restrict HIV-1 infection and provides insight into the specialized role of IFITMs in HIV infection.
    Full-text · Article · Sep 2015 · Cell Reports
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    • "The role of LCK acylation is not restricted to a membranebinding function, since a variant that localizes to the plasma membrane through a transmembrane domain instead of palmitoylation is unable to efficiently reconstitute T-cell receptor signaling (Kabouridis et al., 1997). Interferon-induced transmembrane protein 3 (IFITM3) is involved in innate responses to flu, dengue fever, and West Nile virus (Brass et al., 2009), and it has recently been shown that S-palmitoylation of IFITM3 controls clustering in membrane compartments and its antiviral activity (Yount et al., 2010). Analysis of the family suggests that S-palmitoylation may be an ancient post-translational modification that is crucial for host resistance to viral infections. "
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    ABSTRACT: Protein fatty acylation regulates diverse aspects of cellular function and organization and plays a key role in host immune responses to infection. Acylation also modulates the function and localization of virus-encoded proteins. Here, we employ chemical proteomics tools, bio-orthogonal probes, and capture reagents to study myristoylation and palmitoylation during infection with herpes simplex virus (HSV). Using in-gel fluorescence imaging and quantitative mass spectrometry, we demonstrate a generalized reduction in myristoylation of host proteins, whereas palmitoylation of host proteins, including regulators of interferon and tetraspanin family proteins, was selectively repressed. Furthermore, we found that a significant fraction of the viral proteome undergoes palmitoylation; we identified a number of virus membrane glycoproteins, structural proteins, and kinases. Taken together, our results provide broad oversight of protein acylation during HSV infection, a roadmap for similar analysis in other systems, and a resource with which to pursue specific analysis of systems and functions. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Full-text · Article · Aug 2015 · Chemistry & biology
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