Nemo-like kinase drives Foxp3 stability and is critical for maintenance of immune tolerance by regulatory T cells

Veerle Fleskens, Carlos Munoz Minutti, Xingmei Wu, Ping Wei, Cornelieke E G M Pals, James McCrae, Saskia Hemmers, Vincent Groenewold, Harm-Jan Vos, Alexander Y. Rudensky, Fan Pan, Huabin Li, Dietmar Zaiss, Paul J Coffer

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

The Foxp3 transcription factor is a crucial determinant of both regulatory T (TREG) cell development and their functional maintenance. Appropriate modulation of tolerogenic immune responses therefore requires tight regulation of Foxp3 transcriptional output, and this involves both transcriptional and post-translational regulation. Here, we show that during T cell activation, phosphorylation of Foxp3 in TREG cells can be regulated by a TGFβ Activated Kinase 1 (TAK1)-Nemo Like Kinase (NLK) signaling pathway.
NLK interacts with Foxp3 in TREG cells and directly phosphorylates Foxp3 on multiple serine residues. This phosphorylation results in stabilization of Foxp3 protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase, resulting in both reduced ubiquitination and proteasome-mediated degradation. Conditional TREG cell NLK-knockout (NLKΔTREG) results in decreased TREG cell-mediated immunosuppression in vivo and NLK-deficient TREG cell animals develop more severe experimental autoimmune encephalomyelitis. Our data suggest a molecular mechanism, in which stimulation of TCR-mediated signaling can induce a TAK1-NLK pathway to sustain Foxp3 transcriptional activity through stabilization of protein levels, thereby maintaining TREG cell suppressive function.
Original languageEnglish
Pages (from-to)3600-3612
Number of pages20
JournalCell Reports
Issue number13
Publication statusPublished - 26 Mar 2019

Keywords / Materials (for Non-textual outputs)

  • Treg cell
  • transcription
  • kinase
  • signaling
  • T cell
  • lymphocyte
  • Foxp3
  • phopshorylation
  • NLK
  • Ubiquitination


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