A20 and ABIN-1 cooperate in balancing CBM complex-triggered NF-κB 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-κB 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-κB 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.

  • Yin, H.
  • Karayel, O.
  • Chao, Y. Y.
  • Seeholzer, T.
  • Hamp, I.
  • Plettenburg, O.
  • Gehring, T.
  • Zielinski, C.
  • Mann, M.
  • Krappmann, D.

Keywords

  • B-Cell CLL-Lymphoma 10 Protein/metabolism
  • CARD Signaling Adaptor Proteins/metabolism
  • Cells, Cultured
  • DNA-Binding Proteins/*physiology
  • Guanylate Cyclase/metabolism
  • HEK293 Cells
  • Humans
  • Jurkat Cells
  • Lymphocyte Activation/genetics
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein/metabolism
  • Multiprotein Complexes/metabolism
  • NF-kappa B/metabolism
  • Protein Binding
  • RNA Interference/immunology
  • Signal Transduction/physiology
  • T-Lymphocytes/immunology/*metabolism
  • Tumor Necrosis Factor alpha-Induced Protein 3/*physiology
  • Carma1
  • Immune activation
  • Immune suppression
  • T cell signaling
  • Tnfaip3
  • Tnip1
Publication details
DOI: 10.1007/s00018-022-04154-z
Journal: Cell Mol Life Sci
Pages: 112
Number: 2
Work Type: Original
Access number: 35099607
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