title: Retroviral retention activates a Syk-dependent HemITAM in human tetherin.
abstract: Tetherin (BST2/CD317) restricts the release of enveloped viral particles from infected cells. Coupled to this virion retention, hominid tetherins induce proinflammatory gene expression via activating NF-κB. We investigated the events initiating this tetherin-induced signaling and show that physical retention of retroviral particles induces the phosphorylation of conserved tyrosine residues in the cytoplasmic tails of tetherin dimers. This phosphorylation induces the recruitment of spleen tyrosine kinase (Syk), which is required for downstream NF-κB activation, indicating that the tetherin cytoplasmic tail resembles the hemi-immunoreceptor tyrosine-based activation motifs (hemITAMs) found in C-type lectin pattern recognition receptors. Retroviral-induced tetherin signaling is coupled to the cortical actin cytoskeleton via the Rac-GAP-containing protein RICH2 (ARHGAP44), and a naturally occurring tetherin polymorphism with reduced RICH2 binding exhibits decreased phosphorylation and NF-κB activation. Thus, upon virion retention, this linkage to the actin cytoskeleton likely triggers tetherin phosphorylation and subsequent signal transduction to induce an antiviral state.
authors.affiliation: Department of Infectious Disease, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Rui Pedro
authors.initials: RP
authors.lastname: Galão
authors.affiliation: Department of Infectious Disease, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Pickering
authors.affiliation: School of Biochemistry, Faculty of Medical and Veterinary Sciences, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Curnock
authors.affiliation: Department of Infectious Disease, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK. Electronic address: stuart.neil@kcl.ac.uk.
authors.forename: Stuart J D
authors.initials: SJ
authors.lastname: Neil
mesh_terms: D020816:Amino Acid Motifs; D015703:Antigens, CD / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D058851:GPI-Linked Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D015658:HIV Infections / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C539906:ARHGAP44 protein, human; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C000606896:SYK protein, human