Matsui-Hasumi Akiko, Sato Yayoi, Uto-Konomi Ayako, Yamashita Satoshi, Uehori Junji, Yoshimura Akihiko, Yamashita Masakatsu, Asahara Hiroshi, Suzuki Shinobu, Kubo Masato
Laboratory for Cytokine Regulation, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama-shi, Kanagawa 230-0045, Japan.
Department of Molecular & Cellular Biology, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd, 6-7-5 Minatojima-Minamimachi, Chuo-Ku, Kobe-shi, Hyogo 650-0047, Japan.
Int Immunol. 2017 Mar 1;29(3):133-143. doi: 10.1093/intimm/dxx014.
IL-17 is known to be a cytokine mainly secreted from Th17 cells, which well associate with autoimmune inflammatory responses. In the generation of Th17 cells, RORc and RORa have pivotal roles in controlling the transcription of Il17. We speculated additional regulation in Il17a transcription and randomly screened a 6344 clone cDNA library to identify specific modulators for Il17a promoter activity. After the screen, the E3 ubiquitin ligases SIAH1 and SIAH2 were investigated further and confirmed to increase Il17a promoter activity in a T-cell line and to promote Th17 development ex vivo. This enhancement was a consequence of enhanced expression of hypoxia-inducible factor-1α (HIF-1α) protein, which is reported to directly regulate expression of Il17a and Rorgt at the transcriptional level. In the absence of HIF-1α, both ubiquitin ligases had little effect on Th17 cell differentiation. These results suggest that the SIAH1 and SIAH2 play a pivotal role to promote Th17 cell differentiation through maintaining the stability of HIF-1α protein.
白细胞介素-17（IL-17）是一种主要由辅助性T细胞17（Th17细胞）分泌的细胞因子，与自身免疫性炎症反应密切相关。在Th17细胞的生成过程中，维甲酸相关孤儿受体c（RORc）和维甲酸相关孤儿受体a（RORa）在控制白细胞介素-17（Il17）的转录中起关键作用。我们推测Il17a转录存在额外调控，并随机筛选了一个6344个克隆的cDNA文库，以鉴定Il17a启动子活性的特异性调节因子。筛选后，对E3泛素连接酶SIAH1和SIAH2进行了进一步研究，证实它们可增加T细胞系中Il17a启动子活性，并在体外促进Th17细胞的发育。这种增强是缺氧诱导因子-1α（HIF-1α）蛋白表达增强的结果，据报道该蛋白在转录水平直接调节Il17a和维甲酸相关孤儿受体t（Rorgt）的表达。在缺乏HIF-1α的情况下，这两种泛素连接酶对Th17细胞分化几乎没有影响。这些结果表明，SIAH1和SIAH2通过维持HIF-1α蛋白的稳定性，在促进Th17细胞分化中起关键作用。
