No abstract

a; The Veterans Affairs San Diego Healthcare System, San Diego, California, USA b 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-B activity. Here we show that human BST2 induces NF-B 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-B 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-B. Mutations predicted to disrupt the coiledcoil structure of the BST2 ectodomain impaired both signaling and restriction, but disruption of the tetramerization interface differentially affected signaling BST2 (bone marrow stromal cell antigen 2) (also known as tetherin) is an interferon (IFN)-inducible transmembrane and glycosylphosphatidylinositol (GPI)-anchored protein that restricts the release of several enveloped viruses from infected cells (1, 2). Viruses susceptible to BST2 include all retroviruses so far tested as well as members of the Rhabdoviridae, Paramyxoviridae, Filoviridae, and Herpesviridae families (reviewed in reference 3). Most of these viruses encode BST2 antagonists, which degrade the protein or remove it from the cell surface; the prototype BST2 antagonist is the HIV-1 accessory protein Vpu (1, 2).Although the release of cell-free virions and cell-free infectivity can be dramatically inhibited by BST2, restriction of the cell-tocell spread of virus is less effective (4, 5). This observation calls into question whether restriction of enveloped viruses is the sole function of this protein. Consistent with the possibility of additional functions, BST2 reportedly serves as the ligand for ILT7, a receptor on plasmacytoid dendritic cells that negatively regulates the expression of type I interferon (6). Moreover, BST2 reportedly stimulates the activity of the NF-B family of transcription factors (7), although the determinants of this activity in BST2 and its consequences have until very recently been unknown.Here we confirm that BST2 induces NF-B activity. We show that this activity is genetically separable from the restriction of virion release, yet it requires conserved features of the protein. These features include a YxY motif in the cytoplasmic domain (CD) of BST2 that directs the interaction with a TAK1-and TAB1-containing signaling complex. The BST2 antagonist encoded by HIV-1, Vpu, inhibits the activation of NF-B by BST2 in a manner dependent on its ability to bind the cellular ␤-TrCP-containing, cullin-1-based E3 ubiquitin ligase complex. In the absence of Vpu, however, the expression of HIV-1 augments the activation of NF-B. This suggests that BST2, like the restriction factor Trim5␣ (8), serves not only as ...

The HIV-1 protein Nef inhibits antigen presentation by class I MHC (MHC-I). Here the mechanism of this activity is revealed by the crystal structure of a protein complex consisting of Nef, the MHC-I cytoplasmic domain (MHC-I CD), and the μ1 subunit of the clathrin adaptor protein complex 1. A ternary, cooperative interaction clamps the MHC-I CD into a narrow binding groove at the Nef-μ1 interface encompassing the cargo-recognition site of μ1 and the proline rich strand of Nef. The Nef C-terminus induces a novel conformational change in μ1, while the N-terminus binds the Nef core to position it optimally for complex formation. Positively charged patches on μ1 recognize acidic clusters in Nef and MHC-I. The structure shows how Nef functions as a clathrin-associated sorting protein to alter the specificity of host membrane trafficking and enable viral evasion of adaptive immunity.

European Society of Anaesthesiology.