RESUMO
Virus-infected cells are eliminated by cytotoxic T lymphocytes, which recognize viral epitopes displayed on major histocompatibility complex class I molecules at the cell surface. Herpesviruses have evolved sophisticated strategies to escape this immune surveillance. During the lytic phase of EBV infection, the viral factor BNLF2a interferes with antigen processing by preventing peptide loading of major histocompatibility complex class I molecules. Here we reveal details of the inhibition mechanism of this EBV protein. We demonstrate that BNLF2a acts as a tail-anchored protein, exploiting the mammalian Asna-1/WRB (Get3/Get1) machinery for posttranslational insertion into the endoplasmic reticulum membrane, where it subsequently blocks antigen translocation by the transporter associated with antigen processing (TAP). BNLF2a binds directly to the core TAP complex arresting the ATP-binding cassette transporter in a transport-incompetent conformation. The inhibition mechanism of EBV BNLF2a is distinct and mutually exclusive of other viral TAP inhibitors.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Infecções por Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas da Matriz Viral/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Apresentação de Antígeno/genética , ATPases Transportadoras de Arsenito/genética , ATPases Transportadoras de Arsenito/metabolismo , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/virologia , Infecções por Vírus Epstein-Barr/genética , Células HeLa , Herpesvirus Humano 4/genética , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Complexos Multiproteicos/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Spodoptera , Proteínas da Matriz Viral/genéticaRESUMO
Viral infections are counteracted by virus-specific cytotoxic T cells that recognize the infected cell via MHC class I (MHC I) molecules presenting virus-derived peptides. The loading of the peptides onto MHC I molecules occurs in the endoplasmic reticulum (ER) and is facilitated by the peptide loading complex. A key player in this complex is the transporter associated with antigen processing (TAP), which translocates the viral peptides from the cytosol into the ER. Herpesviruses have developed many strategies to evade cytotoxic T cells. Several members of the genus Varicellovirus encode a UL49.5 protein that prevents peptide transport through TAP. These include bovine herpesvirus (BoHV) 1, BoHV-5, bubaline herpesvirus 1, cervid herpesvirus 1, pseudorabies virus, felid herpesvirus 1, and equine herpesvirus 1 and 4. BoHV-1 UL49.5 inhibits TAP by preventing conformational changes essential for peptide transport and by inducing degradation of the TAP complex. UL49.5 consists of an ER luminal N-terminal domain, a transmembrane domain and a cytosolic C-terminal tail domain. In this study, the following features of UL49.5 were deciphered: (1) chimeric constructs of BoHV-1 and VZV UL49.5 attribute the lack of TAP inhibition by VZV UL49.5 to its ER-luminal domain, (2) the ER-luminal and TM domains of UL49.5 are required for efficient interaction with and inhibition of TAP, (3) the C-terminal RXRX sequence is essential for TAP degradation by BoHV-1 UL49.5, and (4) in addition to the RXRX sequence, the cytoplasmic tail of BoHV-1 UL49.5 carries a motif that is required for efficient TAP inhibition by the protein. A model is presented depicting how the different domains of UL49.5 may block the translocation of peptides by TAP and target TAP for proteasomal degradation.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Varicellovirus/química , Varicellovirus/metabolismo , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/imunologia , Transportadores de Cassetes de Ligação de ATP/imunologia , Linhagem Celular , Separação Celular , Citometria de Fluxo , Humanos , Immunoblotting , Imunoprecipitação , Reação em Cadeia da Polimerase , Estrutura Terciária de Proteína , Transporte Proteico/fisiologia , Varicellovirus/imunologia , Proteínas do Envelope Viral/metabolismoRESUMO
In order to propagate and persist within the host, HIV-1 subverts a variety of checkpoints of innate and adaptive viral immunosurveillance. Many of these are related to natural killer cells, which bridge innate and adaptive immunity and play a major role in defeating virus infections. HIV-1 affects cytotoxicity of natural killer cells towards infected cells and natural killer cell-mediated priming of effector cells of the adaptive immune system. Moreover, a subpopulation of natural killer cells was found sensitive to infection by HIV-1. Consequently, an efficient immune response against HIV-1 cannot be mounted in most patients. The current review highlights the molecular interplay between HIV-1 and effector cells of the host immune system with a focus on natural killer cells, and summarizes strategies of HIV-1 to escape from natural killer cell immunosurveillance. A detailed knowledge of these immune escape strategies might lead to the identification of access points for intervention in order to block infection and progression to AIDS.