m⁶A modification and SUMOylation of PHGDH regulates ulcerative colitis through autophagy

Ulcerative colitis (UC) is a chronic inflammatory bowel disorder with increasing incidence globally. However, the understanding of UC pathogenesis remains limited.

DSS-induced UC mouse model and lipopolysaccharide (LPS)-treated colonic epithelial cell (CEC) model were established. The pathological changes in colons were evaluated by hematoxylin and eosin. Colon injury was graded by pathological scoring, evaluation of colon length and disease activity index. qRT-PCR, Western blot, immunofluorescent staining, and ELISA assay were used to detect the expression and secretion of key molecules. CCK-8 was employed to monitor cell viability. The m⁶A modification of phosphoglycerate dehydrogenase (PHGDH) was assessed by MeRIP assay, and the SUMOylation of PHGDH, as well as the association between PHGDH and ubiquitin conjugating enzyme 9 (UBC9), were detected by co-immunoprecipitation.

PHGDH knockdown alleviated DSS-induced colitis in mice. Inhibiting PHGDH promoted autophagy and inhibited inflammation in DSS-induced colitis and LPS-treated CECs. Methyltransferase-like 3 (METTL3) mediated m⁶A modification of PHGDH in LPS-treated CECs. PHGDH overexpression reversed METTL3 knockdown-facilitated autophagy in the in vitro UC model. Additionally, UBC9-mediated SUMOylation regulated PHGDH protein stability in vitro. Enhanced SUMOylation of PHGDH rescued LPS-impaired cell viability via promoting autophagy. METTL3 inhibited autophagy in LPS-treated CECs by regulating UBC9/PHGDH axis. METTL3 knockdown and UBC9 overexpression synergistically alleviated DSS-induced colon injury. Furthermore, curcumin promoted autophagy via modulating METTL3/UBC9/PHGDH axis, thereby alleviating colonic damage in ulcerative colitis.

m⁶A modification and SUMOylation of PHGDH regulated UC through Beclin-1-dependent autophagy.