PuSH - Publication Server of Helmholtz Zentrum München: A20 intrinsically influences human effector T-cell survival and function by regulating both NF-κB and JNK signaling.

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Dabbah-Krancher, G.* ; Ruchinskas, A.* ; Kallarakal, M.A.* ; Lee, K.P.* ; Bauman, B.M.* ; Epstein, B.* ; Yin, H. ; Krappmann, D. ; Schaefer, B.C.* ; Snow, A.L.*

A20 intrinsically influences human effector T-cell survival and function by regulating both NF-κB and JNK signaling.

Eur. J. Immunol.:e2451245 (2024)

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: Publ. Version/Full Text online available 10/2025

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A20 is a dual-function ubiquitin-editing enzyme that maintains immune homeostasis by restraining inflammation. Although A20 serves a similar negative feedback function for T-cell receptor (TCR) signaling, the molecular mechanisms utilized and their ultimate impact on human T-cell function remain unclear. TCR engagement triggers the assembly of the CARD11-BCL10-MALT1 (CBM) protein complex, a signaling platform that governs the activation of downstream transcription factors including NF-κB and c-Jun/AP-1. Utilizing WT and A20 knockout Jurkat T cells, we found that A20 is required to negatively regulate NF-κB and JNK. Utilizing a novel set of A20 mutants in NF-κB and AP-1-driven reporter systems, we discovered the ZnF7 domain is crucial for negative regulatory capacity, while deubiquitinase activity is dispensable. Successful inactivation of A20 in human primary effector T cells congruently conferred sustained NF-κB and JNK signaling, including enhanced upregulation of activation markers, and increased secretion of several cytokines including IL-9. Finally, loss of A20 in primary human T cells resulted in decreased sensitivity to restimulation-induced cell death and increased sensitivity to cytokine withdrawal-induced death. These findings demonstrate the importance of A20 in maintaining T-cell homeostasis via negative regulation of both NF-κB and JNK signaling.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Apoptosis ; Cellular Immunology ; Cytokines ; Signal Transduction ; T Cells; Transcription Factor Pu.1; Linear Polyubiquitin; Gene-expression; Enzyme A20; Tnfaip3; Binding; Activation; Inhibition; Mutations; Haploinsufficiency

ISSN (print) / ISBN 0014-2980

e-ISSN 1521-4141

Journal European Journal of Immunology

Quellenangaben Article Number: e2451245

Publisher Wiley

Publishing Place Hoboken

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Signaling and Translation (SAT)

Grants NIH Blood Bank - National Institutes of Health
National Institutes of Health