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

Autor: Dabbah-Krancher G; Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, C-2013 Bethesda, MD 20814, USA.; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA., Ruchinskas A; Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, C-2013 Bethesda, MD 20814, USA.; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA., Kallarakal MA; Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, C-2013 Bethesda, MD 20814, USA., Lee KP; Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, C-2013 Bethesda, MD 20814, USA., Bauman BM; Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, C-2013 Bethesda, MD 20814, USA.; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA., Epstein B; Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, C-2013 Bethesda, MD 20814, USA.; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA., Yin H; Research Unit Signaling and Translation, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany., Krappmann D; Research Unit Signaling and Translation, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany., Schaefer BC; Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA., Snow AL; Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, C-2013 Bethesda, MD 20814, USA.
Jazyk: angličtina
Zdroj: European journal of immunology [Eur J Immunol] 2024 Dec; Vol. 54 (12), pp. e2451245. Date of Electronic Publication: 2024 Oct 02.
DOI: 10.1002/eji.202451245
Abstrakt: 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.
(© 2024 Wiley‐VCH GmbH.)
Databáze: MEDLINE
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