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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Hongli Yin
  • Ozge Karayel
  • Ying-Yin Chao
  • Thomas Seeholzer
  • Isabel Hamp
  • Oliver Plettenburg
  • Torben Gehring
  • Christina Zielinski
  • Mann, Matthias
  • Daniel Krappmann

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.

Original languageEnglish
JournalCellular and Molecular Life Sciences
Volume79
Issue number2
Pages (from-to)112
ISSN1420-682X
DOIs
Publication statusPublished - 31 Jan 2022
Externally publishedYes

Bibliographical note

© 2022. The Author(s).

    Research areas

  • 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, Tumor Necrosis Factor alpha-Induced Protein 3/physiology

ID: 303114070