A20 and ABIN-1 cooperate in balancing CBM complex-triggered NF-?B signaling in activated T cells.
T cell activation initiates protective adaptive immunity, but counterbalancing mechanisms are critical to prevent overshooting responses and to maintain immune homeostasis. The CARD11-BCL10-MALT1 (CBM) complex bridges T cell receptor engagement to NF-?B signaling and MALT1 protease activation. Here, we show that ABIN-1 is modulating the suppressive function of A20 in ... T cells. Using quantitative mass spectrometry, we identified ABIN-1 as an interactor of the CBM signalosome in activated T cells. A20 and ABIN-1 counteract inducible activation of human primary CD4 and Jurkat T cells. While A20 overexpression is able to silence CBM complex-triggered NF-?B and MALT1 protease activation independent of ABIN-1, the negative regulatory function of ABIN-1 depends on A20. The suppressive function of A20 in T cells relies on ubiquitin binding through the C-terminal zinc finger (ZnF)4/7 motifs, but does not involve the deubiquitinating activity of the OTU domain. Our mechanistic studies reveal that the A20/ABIN-1 module is recruited to the CBM complex via A20 ZnF4/7 and that proteasomal degradation of A20 and ABIN-1 releases the CBM complex from the negative impact of both regulators. Ubiquitin binding to A20 ZnF4/7 promotes destructive K48-polyubiquitination to itself and to ABIN-1. Further, after prolonged T cell stimulation, ABIN-1 antagonizes MALT1-catalyzed cleavage of re-synthesized A20 and thereby diminishes sustained CBM complex signaling. Taken together, interdependent post-translational mechanisms are tightly controlling expression and activity of the A20/ABIN-1 silencing module and the cooperative action of both negative regulators is critical to balance CBM complex signaling and T cell activation.
Mesh Terms:
B-Cell CLL-Lymphoma 10 Protein, CARD Signaling Adaptor Proteins, Cells, Cultured, DNA-Binding Proteins, Guanylate Cyclase, HEK293 Cells, Humans, Jurkat Cells, Lymphocyte Activation, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Multiprotein Complexes, NF-kappa B, Protein Binding, RNA Interference, Signal Transduction, T-Lymphocytes, Tumor Necrosis Factor alpha-Induced Protein 3
B-Cell CLL-Lymphoma 10 Protein, CARD Signaling Adaptor Proteins, Cells, Cultured, DNA-Binding Proteins, Guanylate Cyclase, HEK293 Cells, Humans, Jurkat Cells, Lymphocyte Activation, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Multiprotein Complexes, NF-kappa B, Protein Binding, RNA Interference, Signal Transduction, T-Lymphocytes, Tumor Necrosis Factor alpha-Induced Protein 3
Cell Mol Life Sci
Date: Jan. 31, 2022
PubMed ID: 35099607
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