ABSTRACT
The stress protein p8 is a small, highly basic, unfolded, and multifunctional protein. We have previously shown that most of its functions are exerted through interactions with other proteins, whose activities are thereby enhanced or repressed. In this work we describe another example of such mechanism, by which p8 binds and negatively regulates MSL1, a histone acetyl transferase (HAT)-associated protein, which in turn binds the DNA-damage-associated 53BP1 protein to facilitate DNA repair following DNA gamma-irradiation. Contrary to the HAT-associated activity, MSL1-dependent DNA-repair activity is almost completely dependent on 53BP1 expression. The picture that has emerged from our findings is that 53BP1 could be a scaffold that gets the HAT MSL1-dependent DNA-repair activity to the sites of DNA damage. Finally, we also found that, although p8 expression is transiently activated after gamma-irradiation, it is eventually submitted to sustained down-regulation, presumably to allow development of MSL1-associated DNA-repair activity. We conclude that interaction of MSL1 with 53BP1 brings MSL1-dependent HAT activity to the vicinity of damaged DNA. MSL1-dependent HAT activity, which is negatively regulated by the stress protein p8, induces chromatin remodeling and relaxation allowing access to DNA of the repair machinery.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/physiology , DNA Breaks, Double-Stranded/radiation effects , DNA Repair/physiology , Gamma Rays , Neoplasm Proteins/physiology , Cell Line , Cell Proliferation , Colony-Forming Units Assay , Gene Expression/genetics , Gene Expression/radiation effects , HeLa Cells , Histone Acetyltransferases/genetics , Histone Acetyltransferases/metabolism , Histones/metabolism , Humans , Immunoprecipitation , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Protein Binding/physiology , RNA, Small Interfering/genetics , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Surface Plasmon Resonance , Transfection , Tumor Suppressor p53-Binding Protein 1 , Two-Hybrid System TechniquesABSTRACT
Survival of lymphocytes after prolonged culture was studied in two asymptomatic XLP patients. Viability of XLP PBMC after 30 days of non-stimulated culture was higher than that of normal controls (N), mainly due to the persistence of CD8 memory lymphocytes. IFNgamma high CD8 T lymphocytes remained higher in XLP than in N after 30 days. The number of perforin+ CD8 lymphocytes was markedly reduced after 30 days in XLP and in N. Increased viability was not related to CD127, PD-1, CD27, or CD62L expression. Concerning B lymphocytes, memory CD27+ CD19+ cells prevailed over CD27- cells after 30 days in both XLP and N, with far more surviving cells in XLP. In N, few CD19+ B lymphocytes were viable after prolonged culture. In XLP, these cells were also IgD+, IgM+ and EBNA2+. These results demonstrate that IFNgamma-positive memory CD8 T cells persist in XLP after prolonged culture in association with a subset of viable memory CD27+ B cells expressing latent EBV antigens. The survival advantage of XLP cells might be related to increased frequency of extranodal lymphoma in XLP patients.
Subject(s)
B-Lymphocytes/pathology , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/pathology , Intracellular Signaling Peptides and Proteins/metabolism , Lymphoproliferative Disorders/pathology , Adult , Antigens, CD/metabolism , Apoptosis Regulatory Proteins/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/virology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Cell Survival , Cells, Cultured , Chromosomes, Human, X/genetics , Epstein-Barr Virus Infections/complications , Humans , Interferon-gamma/metabolism , Interleukin-7 Receptor alpha Subunit/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Lymphoproliferative Disorders/immunology , Lymphoproliferative Disorders/virology , Perforin/metabolism , Programmed Cell Death 1 Receptor , Signaling Lymphocytic Activation Molecule Associated ProteinABSTRACT
Dendritic cells are most important as antigen presenting cells during the induction of an effective immune response. Therefore, it is important to study their role during the generation of persistent or chronic viral infections, such as HIV or HCV infection. In this review we shall describe the phenotypic and functional characteristics of the different classes of dendritic cells and of their membrane receptors. Their participation in defence or facilitation mechanisms involved in the immune response against these viruses will be discussed. It is important to take this knowledge into account when trying to design therapeutic strategies for protection or reconstruction of the immune system that may be altered as a consequence of infection with HIV or HCV.
Subject(s)
Dendritic Cells/immunology , HIV Infections/immunology , Hepatitis C, Chronic/immunology , Cell Differentiation , Cell Lineage/immunology , Cytokines/immunology , Dendritic Cells/cytology , HIV/immunology , Hepacivirus/immunology , Humans , Immunity, Cellular , T-Lymphocytes/immunology , Toll-Like Receptors/immunology , Virus Attachment , Virus InternalizationABSTRACT
Las células dendríticas son las principales células presentadoras de antígenos para el montaje de la respuesta inmune. Por lo tanto es importante estudiar de qué manera intervienen en el equilibrio que el sistema inmune desarrolla frente a infecciones virales persistentes como la infección por el HIV o el HCV. En esta revisión se presentan en primer término generalidades sobre las diferentes clases de células dendríticas, las características fenotípicas y funcionales que las definen y los receptores que pueden estar involucrados en la infección viral. Luego se analiza su participación en los mecanismos de defensa o facilitadores de la infección por estos virus. Es importante tener en cuenta estos conocimientos para poder diseñar adecuadas estrategias de vacunación o protección y para intentar la reconstrucción funcional del sistema inmune impidiendo la subversión de los mecanismos inmunes de defensa causada por la infección con el HIV y el HCV.
Dendritic cells are most important as antigen presenting cells during the induction of an effective immune response. Therefore, it is important to study their role during the generation of persistent or chronic viral infections, such as HIV or HCV infection. In this review we shall describe the phenotypic and functional characteristics of the different classes of dendritic cells and of their membrane receptors. Their participation in defence or facilitation mechanisms involved in the immune response against these viruses will be discussed. It is important to take this knowledge into account when trying to design therapeutic strategies for protection or reconstruction of the immune system that may be altered as a consequence of infection with HIV or HCV.
Subject(s)
Humans , Dendritic Cells/immunology , HIV Infections/immunology , Hepatitis C, Chronic/immunology , Cell Differentiation , Cell Lineage/immunology , Cytokines/immunology , Dendritic Cells/cytology , T-Lymphocytes/immunology , Toll-Like Receptors/immunologyABSTRACT
Las células dendríticas son las principales células presentadoras de antígenos para el montaje de la respuesta inmune. Por lo tanto es importante estudiar de qué manera intervienen en el equilibrio que el sistema inmune desarrolla frente a infecciones virales persistentes como la infección por el HIV o el HCV. En esta revisión se presentan en primer término generalidades sobre las diferentes clases de células dendríticas, las características fenotípicas y funcionales que las definen y los receptores que pueden estar involucrados en la infección viral. Luego se analiza su participación en los mecanismos de defensa o facilitadores de la infección por estos virus. Es importante tener en cuenta estos conocimientos para poder diseñar adecuadas estrategias de vacunación o protección y para intentar la reconstrucción funcional del sistema inmune impidiendo la subversión de los mecanismos inmunes de defensa causada por la infección con el HIV y el HCV.(AU)
Dendritic cells are most important as antigen presenting cells during the induction of an effective immune response. Therefore, it is important to study their role during the generation of persistent or chronic viral infections, such as HIV or HCV infection. In this review we shall describe the phenotypic and functional characteristics of the different classes of dendritic cells and of their membrane receptors. Their participation in defence or facilitation mechanisms involved in the immune response against these viruses will be discussed. It is important to take this knowledge into account when trying to design therapeutic strategies for protection or reconstruction of the immune system that may be altered as a consequence of infection with HIV or HCV. (AU)
