Protein Kinase C Theta Modulates PCMT1 through hnRNPL to Regulate FOXP3 Stability in Regulatory T Cells.

TitleProtein Kinase C Theta Modulates PCMT1 through hnRNPL to Regulate FOXP3 Stability in Regulatory T Cells.
Publication TypeJournal Article
Year of Publication2020
AuthorsE Ozay, I, Shanthalingam, S, Torres, JA, Osborne, BA, Tew, GN, Minter, LM
JournalMol Ther
Date Published2020 10 07
KeywordsCell-Penetrating Peptides, Forkhead Transcription Factors, Gene Expression Regulation, Heterogeneous-Nuclear Ribonucleoprotein L, Promoter Regions, Genetic, Protein Binding, Protein D-Aspartate-L-Isoaspartate Methyltransferase, Protein Kinase C-theta, Protein Stability, Signal Transduction, T-Lymphocytes, Regulatory

T cell receptor signaling, together with cytokine-induced signals, can differentially regulate RNA processing to influence T helper versus regulatory T cell fate. Protein kinase C family members have been shown to function in alternative splicing and RNA processing in various cell types. T cell-specific protein kinase C theta, a molecular regulator of T cell receptor downstream signaling, has been shown to phosphorylate splicing factors and affect post-transcriptional control of T cell gene expression. In this study, we explored how using a synthetic cell-penetrating peptide mimic for intracellular anti-protein kinase C theta delivery fine-tunes differentiation of induced regulatory T cells through its differential effects on RNA processing. We identified protein kinase C theta signaling as a critical modulator of two key RNA regulatory factors, heterogeneous nuclear ribonucleoprotein L (hnRNPL) and protein-l-isoaspartate O-methyltransferase-1 (PCMT1), and loss of protein kinase C theta function initiated a "switch" in post-transcriptional organization in induced regulatory T cells. More interestingly, we discovered that protein-l-isoaspartate O- methyltransferase-1 acts as an instability factor in induced regulatory T cells, by methylating the forkhead box P3 (FOXP3) promoter. Targeting protein-l-isoaspartate O-methyltransferase-1 using a cell-penetrating antibody revealed an efficient means of modulating RNA processing to confer a stable regulatory T cell phenotype.

Alternate JournalMol Ther
PubMed ID32592691
PubMed Central IDPMC7544975