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

Tyrosine phosphorylation and sumoylation modulate c-Maf transactivity on IL-10 and IL-21 gene expression in TH17 cells

劉芷君(Chih-Chun Liu)

指導教授 ： 繆希椿

國立臺灣大學/醫學院/免疫學研究所/博士(2015年)

https://doi.org/10.6342/NTU.2015.10378

摘要

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。

關鍵字

c-Maf ； 酪胺酸磷酸化 ； Sumo化 ； 第十七型輔助T細胞 ； 介白素十 ； 介白素二十一

並列摘要

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.

並列關鍵字

c-Maf ； Tyrosine phosphorylation ； Sumoylation ； IL-10 ； IL-21 ； TH17 cells

參考文獻

Andersen, J.N., Jansen, P.G., Echwald, S.M., Mortensen, O.H., Fukada, T., Del Vecchio, R., Tonks, N.K., and Moller, N.P. (2004). A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 18, 8-30.

Apetoh, L., Quintana, F.J., Pot, C., Joller, N., Xiao, S., Kumar, D., Burns, E.J., Sherr, D.H., Weiner, H.L., and Kuchroo, V.K. (2010). The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat Immunol 11, 854-861.

Bauquet, A.T., Jin, H., Paterson, A.M., Mitsdoerffer, M., Ho, I.C., Sharpe, A.H., and Kuchroo, V.K. (2009). The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat Immunol 10, 167-175.

Bayer, P., Arndt, A., Metzger, S., Mahajan, R., Melchior, F., Jaenicke, R., and Becker, J. (1998). Structure determination of the small ubiquitin-related modifier SUMO-1. J Mol Biol 280, 275-286.

Benkhelifa, S., Provot, S., Lecoq, O., Pouponnot, C., Calothy, G., and Felder-Schmittbuhl, M.P. (1998). mafA, a novel member of the maf proto-oncogene family, displays developmental regulation and mitogenic capacity in avian neuroretina cells. Oncogene 17, 247-254.