NF-κB regulated expression of A20 controls IKK dependent repression of RIPK1 induced cell death in activated T cells.
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
26 Sep 2024
26 Sep 2024
Historique:
received:
21
05
2024
accepted:
16
09
2024
medline:
27
9
2024
pubmed:
27
9
2024
entrez:
26
9
2024
Statut:
aheadofprint
Résumé
IKK signalling is essential for survival of thymocytes by repressing RIPK1 induced cell death rather than its canonical function of activating NF-κB. The role of IKK signalling in activated T cells is unclear. To investigate this, we analysed activation of IKK2 deficient T cells. While TCR triggering was normal, proliferation and expansion was profoundly impaired. This was not due to defective cell cycle progression, rather dividing T cells became sensitised to TNF induced cell death, since inhibition of RIPK1 kinase activity rescued cell survival. Gene expression analysis of activated IKK2 deficient T cells revealed defective expression of Tnfaip3, that encodes A20, a negative regulator of NF-κB. To test whether A20 expression was required to protect IKK2 deficient T cells from cell death, we generated mice with T cells lacking both A20 and IKK2. Doing this resulted in near complete loss of peripheral T cells, in contrast to mice lacking one or other gene. Strikingly, this phenotype was completely reversed by inactivation of RIPK1 kinase activity in vivo. Together, our data show that IKK signalling in activated T cells protects against RIPK1 dependent death, both by direct phosphorylation of RIPK1 and through NF-κB mediated induction of A20, that we identify for the first time as a key modulator of RIPK1 activity in T cells.
Identifiants
pubmed: 39327505
doi: 10.1038/s41418-024-01383-6
pii: 10.1038/s41418-024-01383-6
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : RCUK | Medical Research Council (MRC)
ID : MR/P011225/1
Organisme : RCUK | Medical Research Council (MRC)
ID : MR/P011225/1
Informations de copyright
© 2024. The Author(s).
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