Targeting glucose metabolism in Th17 cells may be beneficial for treating inflammatory bowel disease (IBD) and colitis-associated cancer (CAC), however, the molecular mechanisms orchestrating Th17 cell metabolism remain unclear. Here, we revealed that HECTD1 regulates IGF2BP3-dependent HIF-1α translation to promote Th17 cell glycolysis and differentiation and that HECTD1 expression correlates with IBD and CAC pathogenesis. T-cell-specific deletion of HECTD1 mitigated the severity of colitis and CAC in murine models. RNA-seq revealed enrichment of Th17 differentiation, glycolysis/gluconeogenesis, and HIF-1 signaling pathways among differentially expressed genes between HECTD1-sufficient and HECTD1-deficient CD4... More
Targeting glucose metabolism in Th17 cells may be beneficial for treating inflammatory bowel disease (IBD) and colitis-associated cancer (CAC), however, the molecular mechanisms orchestrating Th17 cell metabolism remain unclear. Here, we revealed that HECTD1 regulates IGF2BP3-dependent HIF-1α translation to promote Th17 cell glycolysis and differentiation and that HECTD1 expression correlates with IBD and CAC pathogenesis. T-cell-specific deletion of HECTD1 mitigated the severity of colitis and CAC in murine models. RNA-seq revealed enrichment of Th17 differentiation, glycolysis/gluconeogenesis, and HIF-1 signaling pathways among differentially expressed genes between HECTD1-sufficient and HECTD1-deficient CD4+ T cells. Consistently, loss of HECTD1 suppressed Th17 cell differentiation both in vitro and in vivo, and suppressed glycolytic metabolism and HIF-1α activity, revealing the mechanism underlying its protective effects against IBD and CAC. Mechanistically, HECTD1 potentiates m6A-based HIF-1α translation by mediating IGF2BP3 K63-linked ubiquitination to promote the binding of IGF2BP3 with the translation initiation machinery of Hif1a mRNA. Reciprocally, HIF-1α acts as a key transcription factor that promotes Hectd1 gene expression, establishing a distinct positive feedback loop. Our findings highlight a self-reinforcing feedback mechanism in which HECTD1 and HIF-1α engage in mutual regulation to dictate Th17 cell fate and metabolic reprogramming, providing novel potential IBD and CAC treatments targeting HECTD1.
