title: Snapin, positive regulator of stimulation- induced Ca²⁺ release through RyR, is necessary for HIV-1 replication in T cells.
abstract: To identify critical host factors necessary for human immunodeficiency virus 1 (HIV-1) replication, large libraries of short-peptide-aptamers were expressed retrovirally. The target of one inhibitor peptide, Pep80, identified in this screen was determined to be Snapin, a protein associated with the soluble N-ethyl maleimide sensitive factor adaptor protein receptor (SNARE) complex that is critical for calcium-dependent exocytosis during neurotransmission. Pep80 inhibited Ca²⁺ release from intracellular stores and blocked downstream signaling by direct interruption of the association between Snapin and an intracellular calcium release channel, the ryanodine receptor (RyR). NFAT signaling was preferentially abolished by Pep80. Expression of Snapin overcame Pep80-mediated inhibition of Ca²⁺/NFAT signaling and HIV-1 replication. Furthermore, Snapin induced HIV-1 replication in primary CD4⁺ T cells. Thus, through its interaction with RyR, Snapin is a critical regulator of Ca²⁺ signaling and T cell activation. Use of the genetically selected intracellular aptamer inhibitors allowed us to define unique mechanisms important to HIV-1 replication and T cell biology.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America ; Laboratory of Immune Regulation, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka, Japan.
authors.forename: Shigemi M
authors.initials: SM
authors.lastname: Kinoshita
authors.forename: Amane
authors.initials: A
authors.lastname: Kogure
authors.forename: Shizuka
authors.initials: S
authors.lastname: Taguchi
authors.forename: Garry P
authors.initials: GP
authors.lastname: Nolan
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D005434:Flow Cytometry; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D019169:Jurkat Cells; D018613:Microscopy, Confocal; D011485:Protein Binding; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism* / Q000821:virology*; D020798:Two-Hybrid System Techniques; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; C118519:SNAPIN protein, human; D033921:Vesicular Transport Proteins; D002118:Calcium