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Publication

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

Cell reports | 2019

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.

Pubmed ID: 30917315 RIS Download

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Associated grants

Agency: Howard Hughes Medical Institute, United States
Agency: NCI NIH HHS, United States
Id: P30 CA008748
Agency: NIAID NIH HHS, United States
Id: R01 AI137046
Agency: Medical Research Council, United Kingdom
Id: MR/M018911/1
Agency: Medical Research Council, United Kingdom
Id: MR/M011755/1

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