title: Mice with disrupted type I protein kinase A anchoring in T cells resist retrovirus-induced immunodeficiency.
abstract: Type I protein kinase A (PKA) is targeted to the TCR-proximal signaling machinery by the A-kinase anchoring protein ezrin and negatively regulates T cell immune function through activation of the C-terminal Src kinase. RI anchoring disruptor (RIAD) is a high-affinity competitor peptide that specifically displaces type I PKA from A-kinase anchoring proteins. In this study, we disrupted type I PKA anchoring in peripheral T cells by expressing a soluble ezrin fragment with RIAD inserted in place of the endogenous A-kinase binding domain under the lck distal promoter in mice. Peripheral T cells from mice expressing the RIAD fusion protein (RIAD-transgenic mice) displayed augmented basal and TCR-activated signaling, enhanced T cell responsiveness assessed as IL-2 secretion, and reduced sensitivity to PGE(2)- and cAMP-mediated inhibition of T cell function. Hyperactivation of the cAMP-type I PKA pathway is involved in the T cell dysfunction of HIV infection, as well as murine AIDS, a disease model induced by infection of C57BL/6 mice with LP-BM5, a mixture of attenuated murine leukemia viruses. LP-BM5-infected RIAD-transgenic mice resist progression of murine AIDS and have improved viral control. This underscores the cAMP-type I PKA pathway in T cells as a putative target for therapeutic intervention in immunodeficiency diseases.
authors: The Biotechnology Center of Oslo, University of Oslo, N-0317 Oslo, Norway.
authors: Randi
authors: R
authors: Mosenden
authors: Pratibha
authors: P
authors: Singh
authors: Isabelle
authors: I
authors: Cornez
authors: Mikael
authors: M
authors: Heglind
authors: Anja
authors: A
authors: Ruppelt
authors: Michel
authors: M
authors: Moutschen
authors: Sven
authors: S
authors: Enerbäck
authors: Souad
authors: S
authors: Rahmouni
authors: Kjetil
authors: K
authors: Taskén
mesh_terms: D054758:A Kinase Anchor Proteins / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D003598:Cytoskeletal Proteins / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016183:Murine Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D000099149:Ezrin
chemical_list: D054758:A Kinase Anchor Proteins; D003598:Cytoskeletal Proteins; D000099149:Ezrin