Abstract
SummaryAntiviral proteins that recognize pathogen-specific or aberrantly located molecular motifs are perfectly positioned to act as pattern-recognition receptors and signal to the immune system. Here we investigated whether the interferon-induced viral restriction factor tetherin (CD317/BST2), which is known to inhibit HIV-1 particle release by physically tethering virions to the cell surface, has such a signaling role. We find that upon restriction of Vpu-defective HIV-1, tetherin acts as a virus sensor to induce NFκB-dependent proinflammatory gene expression. Signaling requires both tetherin’s extracellular domain involved in virion retention and determinants in the cytoplasmic tail, including an endocytic motif, although signaling is independent of virion endocytosis. Furthermore, recruitment of the TNF-receptor-associated factor TRAF6 and activation of the mitogen-activated protein kinase TAK1 are critical for signaling. Human tetherin’s ability to mediate efficient signaling may have arisen as a result of a five amino acid deletion that occurred in hominids after their divergence from chimpanzees.
Highlights
Tetherin is a broadly acting antiviral membrane protein that blocks the release of diverse mammalian viruses from the surface of infected cells and reduces retroviral pathogenesis in vivo (Liberatore and Bieniasz, 2011; Martin-Serrano and Neil, 2011)
Restriction of Enveloped Virus Particle Release by Human Tetherin Induces NFkB-Dependent Gene Expression We first sought to confirm whether tetherin was capable of inducing NFkB activation when overexpressed
Transient transfection of human tetherin into 293 cells potently induced the activation of an NFkB-dependent firefly luciferase reporter construct to levels similar to those seen with the MAVS/IPS1/ Cardif component of the cytoplasmic viral RNA-sensing pathway (Takeuchi and Akira, 2010), confirming the previous observation from the genomic screen (Matsuda et al, 2003) (Figure 1A)
Summary
Tetherin is a broadly acting antiviral membrane protein that blocks the release of diverse mammalian viruses from the surface of infected cells and reduces retroviral pathogenesis in vivo (Liberatore and Bieniasz, 2011; Martin-Serrano and Neil, 2011). The potential importance of tetherin in innate antiviral immunity is underscored by examples of virally encoded proteins that counteract its activity, the prototype being the accessory gene product Vpu of human immunodeficiency virus type 1 (HIV-1) (Le Tortorec et al, 2011). Vpu interacts with human tetherin in infected cells, blocking its transit to viral assembly sites on the PM (Dubeet al., 2011; Kueck and Neil, 2012; Schmidt et al, 2011) and promoting its endosomal degradation (Agromayor et al, 2012; Janvier et al, 2011). In SIVs in which Vpu is absent, the Nef accessory protein performs the role, and the sensitivity of primate tetherins to SIV Nefs is determined by a five amino acid patch in the protein’s cytoplasmic tail that was deleted after hominids and chimpanzees diverged (Jia et al, 2009; Zhang et al, 2009)
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