title: Deltex1 promotes protein kinase Cθ degradation and sustains Casitas B-lineage lymphoma expression.
abstract: The generation of T cell anergy is associated with upregulation of ubiquitin E3 ligases including Casitas B-lineage lymphoma (Cbl-b), Itch, gene related to anergy in lymphocyte, and deltex1 (DTX1). These E3 ligases attenuate T cell activation by targeting to signaling molecules. For example, Cbl-b and Itch promote the degradation of protein kinase Cθ (PKCθ) and phospholipase C-γ1 (PLC-γ1) in anergic Th1 cells. How these anergy-associated E3 ligases coordinate during T cell anergy remains largely unknown. In the current study, we found that PKCθ and PLC-γ1 are also downregulated by DTX1. DTX1 interacted with PKCθ and PLC-γ1 and stimulated the degradation of PKCθ and PLC-γ1. T cell anergy-induced proteolysis of PKCθ was prevented in Dtx1(-/-) T cells, supporting the essential role of DTX1 in PKCθ downregulation. Similar to Cbl-b and Itch, DTX1 promoted monoubiquitination of PKCθ. Proteasome inhibitor did not inhibit DTX1-directed PKCθ degradation, but instead DTX1 directed the relocalization of PKCθ into the lysosomal pathway. In addition, DTX1 interacted with Cbl-b and increased the protein levels of Cbl-b. We further demonstrated the possibility that, through the downregulation of PKCθ, DTX1 prevented PKCθ-induced Cbl-b degradation and increased Cbl-b protein stability. Our results suggest the coordination between E3 ligases during T cell anergy; DTX1 acts with Cbl-b to assure a more extensive silencing of PKCθ, whereas DTX1-mediated PKCθ degradation further stabilizes Cbl-b.
authors.affiliation: Institute of Immunology, National Taiwan University College of Medicine, Taipei 10051, Taiwan, Republic of China; Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China; and.
authors.forename: Tzu-Sheng
authors.initials: TS
authors.lastname: Hsu
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China; and.
authors.forename: Huey-Wen
authors.initials: HW
authors.lastname: Hsiao
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China; and Institute of Life Sciences, National Defense Medical College, Taipei, Taiwan 114, Republic of China.
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Wu
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China; and.
authors.forename: Wen-Hsien
authors.initials: WH
authors.lastname: Liu
authors.affiliation: Institute of Immunology, National Taiwan University College of Medicine, Taipei 10051, Taiwan, Republic of China; Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China; and Institute of Life Sciences, National Defense Medical College, Taipei, Taiwan 114, Republic of China mblai@imb.sinica.edu.tw.
authors.forename: Ming-Zong
authors.initials: MZ
authors.lastname: Lai
mesh_terms: D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002460:Cell Line; D017635:Clonal Anergy; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D015536:Down-Regulation; D057809:HEK293 Cells; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D008247:Lysosomes / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D050722:Oncogene Protein v-cbl / Q000096:biosynthesis* / Q000235:genetics; D051966:Phospholipase C gamma / Q000096:biosynthesis / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D059748:Proteolysis; D034622:RNA Interference; D034741:RNA, Small Interfering; D018417:Th1 Cells / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics; D054875:Ubiquitination; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000096:biosynthesis
chemical_list: D004268:DNA-Binding Proteins; D007527:Isoenzymes; D050722:Oncogene Protein v-cbl; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D000001:Calcimycin; C471637:Itch protein, mouse; C104035:Dtx1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D051966:Phospholipase C gamma