Nemo-like Kinase Drives Foxp3 Stability and Is Critical for Maintenance of Immune Tolerance by Regulatory T Cells.

Journal Article (Journal Article)

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 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 TREG cells can be regulated by a TGF-β activated kinase 1 (TAK1)-Nemo-like kinase (NLK) signaling pathway. NLK interacts and phosphorylates Foxp3 in TREG cells, resulting in the stabilization of protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase. 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 the stabilization of protein levels, thereby maintaining TREG cell suppressive function.

Full Text

Duke Authors

Cited Authors

  • Fleskens, V; Minutti, CM; Wu, X; Wei, P; Pals, CEGM; McCrae, J; Hemmers, S; Groenewold, V; Vos, H-J; Rudensky, A; Pan, F; Li, H; Zaiss, DM; Coffer, PJ

Published Date

  • March 26, 2019

Published In

Volume / Issue

  • 26 / 13

Start / End Page

  • 3600 - 3612.e6

PubMed ID

  • 30917315

Pubmed Central ID

  • PMC6444001

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2019.02.087

Language

  • eng

Conference Location

  • United States