探討c-Maf酪胺酸磷酸化與Sumo化於第十七型輔助T細胞產生介白素十與介白素二十一之調控

Abstract

c-Maf是具有basic leucine zipper的轉錄因子，在第二型輔助T細胞中是介白素四重要及專一的調控因子。在第二型輔助T細胞中發現，c-Maf中第21/92/131酪胺酸的磷酸化增加c-Maf聚集於DNA，使得c-Maf轉錄介白素四基因能力增強。另一方面c-Maf中第33的離胺酸可被Ubc9及PIAS1等Sumo相關之酵素進行Sumo化修飾， Sumo化修飾降低c-Maf聚集於DNA上，導致c-Maf 轉錄介白素四的能力降低。然而，c-Maf在其他的輔助型T細胞是否也會進行酪胺酸磷酸化及Sumo化，以及這兩種後轉譯修飾是否影響c-Maf的轉錄活性仍有待闡明。在我的研究中證實，c-Maf 的酪胺酸磷酸化可發生於第十七型輔助T細胞中，並正向增強介白素十及介白素二十一基因之表達。此外Tec kinase在此被證明是c-Maf的酪胺酸激酶，可對c-Maf直接進行酪胺酸磷酸化。Tec kinase和 Ptpn22交互調節c-Maf的酪胺酸磷酸化，而Ptpn22則抵消Tec kinase所增強之c-Maf的轉錄能力。另一方面，第十七型輔助T細胞中， Sumo化修飾扮演負向調控c-Maf於介白素十及介白素二十一基因的轉錄能力。

c-Maf, containing basic leucine zipper, is an important and specific transcription factor of Interleukin-4 (IL-4) in T helper 2 (TH2) cells. The phosphorylation at the tyrosine residues 21/92/131 of c-Maf enhances IL-4 gene expression via increasing recruitment of c-Maf on IL-4 promoter. On the other hand, the lysine residue 33 of c-Maf is the substrate of Ubc9 and PIAS1 that are the enzymes of sumoylation. Sumoylation represses the transactivity of c-Maf on IL-4 gene expression through reducing recruitment of c-Maf on IL-4 promoter. However, whether tyrosine phosphorylation and sumoylation of c-Maf undergo in other helper T cell subsets remains unknown. In this thesis, I demonstrated that the phosphorylation at tyrosine residues 21/92/131 of c-Maf enhances the IL-10 and IL-21 production in TH17 cells. Furthermore, that the Tec kinase (Tec) and protein tyrosine phosphatase non-receptor type 22 (Ptpn22) modulate c-Maf was characterized. Tec kinase and Ptpn22 act reciprocally in regulating the tyrosine phosphorylation and transactivity of c-Maf. Conversely, sumoylation represses the c-Maf dependent IL-10 and IL-21 production in TH17 cells.