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

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

Cell. Mol. Life Sci. 79:112 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Carma1 ; Immune Activation ; Immune Suppression ; T Cell Signaling ; Tnfaip3 ; Tnip1; Modifying Enzyme A20; Ubiquitin-binding; A20-binding Inhibitor; Linear Polyubiquitin; Malt1 Paracaspase; Receptor; Inflammation; Lymphocytes; Recruitment; Expression
ISSN (print) / ISBN 1420-682X
e-ISSN 1420-9071
Journal Cellular and Molecular Life Sciences - CMLS
Quellenangaben Volume: 79, Issue: 2, Pages: , Article Number: 112 Supplement: ,
Publisher Birkhäuser
Publishing Place Picassoplatz 4, Basel, 4052, Switzerland
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Signaling and Translation (SAT)
Institute of Molecular Toxicology and Pharmacology (TOXI)
Institute of Medicinal Chemistry (IMC)
Grants Deutsche Forschungsgemeinschaft