E3 ubiquitin ligases SIAH1/2 regulate hypoxia-inducible factor-1 (HIF-1)-mediated T h 17 cell differentiation

<span class="paragraphSection"><div class="boxTitle">Abstract</div>IL-17 is known to be a cytokine mainly secreted from T_h17 cells, which well associate with autoimmune inflammatory responses. In the generation of T_h17 cells, RORc and RORa have pivotal roles in controlling the transcription of <span style="font-style:italic;">Il17</span>. We speculated additional regulation in <span style="font-style:italic;">Il17a</span> transcription and randomly screened a 6344 clone cDNA library to identify specific modulators for <span style="font-style:italic;">Il17a</span> promoter activity. After the screen, the E3 ubiquitin ligases SIAH1 and SIAH2 were investigated further and confirmed to increase <span style="font-style:italic;">Il17a</span> promoter activity in a T-cell line and to promote T_h17 development <span style="font-style:italic;">ex vivo</span>. This enhancement was a consequence of enhanced expression of hypoxia-inducible factor-1α (HIF-1α) protein, which is reported to directly regulate expression of <span style="font-style:italic;">Il17a</span> and <span style="font-style:italic;">Rorgt</span> at the transcriptional level. In the absence of HIF-1α, both ubiquitin ligases had little effect on T_h17 cell differentiation. These results suggest that the SIAH1 and SIAH2 play a pivotal role to promote T_h17 cell differentiation through maintaining the stability of HIF-1α protein.</span>

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