cop9 signalosome component jab1csn5 is necessary for t cell signaling through lfa-1 and hiv-1 replicationcop9 signalosome组件jab1csn5 t细胞所必需的信号通过lfa-1和hiv - 1复制.pdfVIP

COP9 Signalosome Component JAB1/CSN5 Is Necessary for T Cell Signaling through LFA-1 and HIV-1 Replication 1,2 3 3,4 Shigemi M. Kinoshita *, Peter O. Krutzik , Garry P. Nolan 1 Laboratory of Immune Regulation, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka, Japan, 2 Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America, 3 Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, California, United States of America, 4 Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America Abstract To determine critical host factors involved in HIV-1 replication, a dominant effector genetics approach was developed to reveal signaling pathways on which HIV-1 depends for replication. A large library of short peptide aptamers was expressed via retroviral delivery in T cells. Peptides that interfered with T cell activation-dependent processes that might support HIV-1 replication were identified. One of the selected peptides altered signaling, lead to a difference in T cell activation status, and inhibited HIV-1 replication. The target of the peptide was JAB1/CSN5, a component of the signalosome complex. JAB1 expression overcame the inhibition of HIV-1 replication in the presence of peptide and also promoted HIV-1 replication in activated primary CD4+ T cells. This peptide blocked physiological release of JAB1 from the accessory T cell surface protein LFA-1, downstream AP-1 dependent events, NFAT activation, and HIV-1 replication. Thus, genetic selection for intracellular aptamer inhibitors of host cell processes proximal to signals at the immunological synapse of T cells can define