title: Stimulation of NF-κB activity by the HIV restriction factor BST2.
abstract: BST2 (HM1.24; CD317; tetherin) is an interferon-inducible transmembrane protein that restricts the release of several enveloped viruses, including HIV, from infected cells. Before its activity as an antiviral factor was described, BST2 was identified as an inducer of NF-κB activity. Here we show that human BST2 induces NF-κB in a dose-dependent manner. This activity is separable from the restriction of virus release: a YxY sequence in the cytoplasmic domain of BST2 is required for the induction of NF-κB but is dispensable for restriction, whereas the glycosylphosphatidylinositol (GPI) addition site in the protein's ectodomain is required for restriction but is largely dispensable for the induction of NF-κB. Mutations predicted to disrupt the coiled-coil structure of the BST2 ectodomain impaired both signaling and restriction, but disruption of the tetramerization interface differentially affected signaling. The induction of NF-κB by BST2 was impaired by inhibition of transforming growth factor β (TGF-β)-activated kinase 1 (TAK1) or by calcium chelation, suggesting potential linkage to the mitogen-activated protein kinase and endoplasmic reticulum (ER) stress response pathways. Consistent with a role for TAK1, BST2 coimmunoprecipitated with TAK1 and the TAK1-associated pseudophosphatase TAB1; these interactions required the YxY sequence in BST2. Moreover, signaling by BST2 was blocked by expression of an IκB-mutant that inhibits the canonical pathway of NF-κB activation. The expression of HIV-1 Vpu inhibited the induction of NF-κB by BST2; this inhibition required Vpu's ability to bind the cellular β-TrCP-E3-ubiquitin ligase complex. The expression of HIV-1 lacking vpu augmented the induction of NF-κB activity by BST2, suggesting that BST2 can act as a virus sensor. This augmentation was also inhibited by Vpu in a β-TrCP-dependent manner. The role of BST2 in the host-pathogen relationship is apparently multifaceted: signaling during the innate immune response, sensing of viral gene expression, and direct restriction of virus release. HIV-1 Vpu counteracts each of these functions.
authors.affiliation: The University of California-San Diego, La Jolla California, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Tokarev
authors.forename: Marissa
authors.initials: M
authors.lastname: Suarez
authors.forename: Wilson
authors.initials: W
authors.lastname: Kwan
authors.forename: Kathleen
authors.initials: K
authors.lastname: Fitzpatrick
authors.forename: Rajendra
authors.initials: R
authors.lastname: Singh
authors.forename: John
authors.initials: J
authors.lastname: Guatelli
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD / Q000378:metabolism*; D002460:Cell Line; D058851:GPI-Linked Proteins / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology; D054298:Human Immunodeficiency Virus Proteins / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B / Q000096:biosynthesis*; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D054334:Viral Regulatory and Accessory Proteins; D000099151:MAP Kinase Kinase Kinase 7; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C486300:TAB1 protein, human; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins