Title | Protein Kinase C Theta Modulates PCMT1 through hnRNPL to Regulate FOXP3 Stability in Regulatory T Cells. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | E Ozay, I, Shanthalingam, S, Torres, JA, Osborne, BA, Tew, GN, Minter, LM |
Journal | Mol Ther |
Volume | 28 |
Issue | 10 |
Pagination | 2220-2236 |
Date Published | 2020 10 07 |
ISSN | 1525-0024 |
Keywords | Cell-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 |
Abstract | 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. |
DOI | 10.1016/j.ymthe.2020.06.012 |
Alternate Journal | Mol Ther |
PubMed ID | 32592691 |
PubMed Central ID | PMC7544975 |
Veterinary and Animal Sciences