title: Innate sensing of HIV-1 assembly by Tetherin induces NFκB-dependent proinflammatory responses.
abstract: Antiviral 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.
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.forename: Anna
authors.initials: A
authors.lastname: Le Tortorec
authors.forename: Suzanne
authors.initials: S
authors.lastname: Pickering
authors.forename: Tonya
authors.initials: T
authors.lastname: Kueck
authors.forename: Stuart J D
authors.initials: SJ
authors.lastname: Neil
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004705:Endocytosis; D058851:GPI-Linked Proteins / Q000378:metabolism; D057809:HEK293 Cells; D015497:HIV-1 / Q000378:metabolism* / Q000502:physiology*; D006367:HeLa Cells; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics*; D006801:Humans; D007249:Inflammation; D020930:MAP Kinase Kinase Kinases; D008251:Macaca; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D002679:Pan troglodytes; D034622:RNA Interference; D034741:RNA, Small Interfering; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics*; D019065:Virus Assembly; D014779:Virus Replication; D000099151:MAP Kinase Kinase Kinase 7; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051192:Receptors, Pattern Recognition; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D044763:Ubiquitin-Conjugating Enzymes; D054334:Viral Regulatory and Accessory Proteins; D000099151:MAP Kinase Kinase Kinase 7; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins; C471607:UBE2N protein, human