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


Authors: Fleskens, V.; Minutti, C. M.; Wu, X.; Wei, P.; Pals, C. E. G. M.; McCrae, J.; Hemmers, S.; Groenewold, V.; Vos, H. J.; Rudensky, A.; Pan, F.; Li, H.; Zaiss, D. M.; Coffer, P. J.
Article Title: Nemo-like kinase drives Foxp3 stability and is critical for maintenance of immune tolerance by regulatory T cells
Abstract: The Foxp3 transcription factor is a crucial determinant of both regulatory T (T REG ) cell development and their functional maintenance. Appropriate modulation of tolerogenic immune responses therefore requires the 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 T REG cells can be regulated by a TGF-β activated kinase 1 (TAK1)-Nemo-like kinase (NLK) signaling pathway. NLK interacts and phosphorylates Foxp3 in T REG cells, resulting in the stabilization of protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase. Conditional T REG cell NLK-knockout (NLK ΔTREG ) results in decreased T REG cell-mediated immunosuppression in vivo, and NLK-deficient T REG 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 the stabilization of protein levels, thereby maintaining T REG cell suppressive function. The maintenance of Foxp3 expression is critical for correct T REG cell function. Fleskens et al. demonstrate a molecular mechanism in which TCR engagement can stabilize Foxp3 protein expression through TAK1-NLK-regulated phosphorylation, thereby maintaining T REG cell suppressive function. © 2019 The Authors
Keywords: phosphorylation; immune tolerance; ubiquitination; foxp3; tcr; nlk; regulatory t cell
Journal Title: Cell Reports
Volume: 26
Issue: 13
ISSN: 2211-1247
Publisher: Cell Press  
Date Published: 2019-03-26
Start Page: 3600
End Page: 3612.e6
Language: English
DOI: 10.1016/j.celrep.2019.02.087
PROVIDER: scopus
PUBMED: 30917315
DOI/URL:
Notes: Source: Scopus
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MSK Authors
  1. Alexander Rudensky
    100 Rudensky
  2. Saskia Hemmers
    13 Hemmers