Phosphorylation by CDK2 destabilises Foxp3
CDK2-KO Tregs were previously reported to be functionally defective. Sequence analysis revealed cluster of 4 CDK motifs in N-terminal domain, 2 shown to be phosphorylated by CDK2/cyclin E complex.
Foxp3 with all 4 Ser/Thr residues mutated to alanine (S/T-->A) show increased protein half-life in cycloheximide-treated cells/amount of protein in cells, with no change in gene transcription.
S/T-->A Foxp3 transfected into naive Tcon - induces stronger expression/repression of Foxp3 target genes than WT - exerts stronger suppression on Tcon proliferation - results in more complete recovery of colitis in Rag1KO mice transferred with Tcon
Hypothesised mechanism of destabilisation: CDK2 phosphorylation primes ubiquitination by E3 as a ‘phospho-degron’ - precedent in cyclin E.
Thymic Tregs repress expression of CDKs - to maintain Foxp3 stability? TGFb induces expression of p27kip1 which inhibits CDK2.
Fig 4
INTERESTING: Another example of phosphorylation affecting Foxp3 function. Does this mechanism have an adaptive role in Tregs in an active immune response, or is it more for the purposes of differentiation? Is CDK2 (or other CDKs) expression/activity triggered by immune activation or only cell cycle?
Source: Morawski, Peter (Wells, Andrew) 2013 J Biol Chem. Foxp3 Protein Stability Is Regulated by Cyclin-dependent Kinase 2 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750148/
