A20 and ABIN-1 cooperate in balancing CBM complex-triggered NF-κB signaling in activated T cells

Cell Mol Life Sci. 2022 Jan 31;79(2):112. doi: 10.1007/s00018-022-04154-z.


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.

Keywords: CARMA1; Immune activation; Immune suppression; T cell signaling; TNFAIP3; TNIP1.

MeSH terms

  • 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
  • T-Lymphocytes / metabolism*
  • Tumor Necrosis Factor alpha-Induced Protein 3 / physiology*


  • B-Cell CLL-Lymphoma 10 Protein
  • BCL10 protein, human
  • CARD Signaling Adaptor Proteins
  • DNA-Binding Proteins
  • Multiprotein Complexes
  • NF-kappa B
  • TNIP1 protein, human
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • MALT1 protein, human
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • CARD11 protein, human
  • Guanylate Cyclase