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: Tzu-Sheng Hsu, Huey-Wen Hsiao, Pei-Jung Wu, Wen-Hsien Liu, Ming-Zong Lai
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 193 Issue 4 Pg. 1672-80 (Aug 15 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 25000980 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by The American Association of Immunologists, Inc.

Chemical References

• DNA-Binding Proteins
• Isoenzymes
• Oncogene Protein v-cbl
• Proteasome Inhibitors
• RNA, Small Interfering
• Calcimycin
• Itch protein, mouse
• Dtx1 protein, mouse
• Ubiquitin-Protein Ligases
• ZAP-70 Protein-Tyrosine Kinase
• ZAP70 protein, human
• Prkcq protein, mouse
• Protein Kinase C
• Protein Kinase C-theta
• Phospholipase C gamma

Topics

• Animals
• Calcimycin (pharmacology)
• Cell Line
• Clonal Anergy
• DNA-Binding Proteins (biosynthesis, genetics)
• Down-Regulation
• HEK293 Cells
• Humans
• Isoenzymes (biosynthesis, genetics, metabolism)
• Jurkat Cells
• Lymphocyte Activation (immunology)
• Lysosomes (immunology)
• Mice
• Mice, Knockout
• Oncogene Protein v-cbl (biosynthesis, genetics)
• Phospholipase C gamma (biosynthesis, metabolism)
• Proteasome Inhibitors (pharmacology)
• Protein Kinase C (biosynthesis, genetics, metabolism)
• Protein Kinase C-theta
• Proteolysis
• RNA Interference
• RNA, Small Interfering
• Th1 Cells (immunology)
• Ubiquitin-Protein Ligases (biosynthesis, genetics)
• Ubiquitination
• ZAP-70 Protein-Tyrosine Kinase (biosynthesis)