Title E 3 ubiquitin ligases SIAH 1 / 2 regulates hypoxia-inducible factor 1 ( HIF 1 )-mediated T H 17 cell differentiation Running title SIAH 1 / 2 regulates HIF 1-mediated T H 17 cell differentiation

IL-17 is known to be a cytokine mainly secreting 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 IL-17. We speculated additional regulation in IL-17A transcription and randomly screened a 6,344 clone cDNA library to identify specific modulators for IL-17A promoter activity. After the screen, the E3 ubiquitin ligases SIAH1 and SIAH2 were investigated further and confirmed to increase IL-17A promoter activity in T cell line and to promote TH17 development ex vivo. This enhancement was a consequence of enhanced expression of hypoxia-inducible factor 1 (HIF-1) protein, which is reported to directly regulate expression of Il17a and Rorgt in 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 a stability of HIF-1 protein.