Neddylation E2 enzyme UBE2F promotes colitis and colon tumorigenesis by targeting the PTPRN-pSTAT5 axis

Whether and how neddylation enzyme mechanistically regulates the process of these diseases are largely elusive. Here we report that UBE2F, a neddylation conjugation enzyme, plays a promoting role.

UBE2F expression is significantly upregulated in IBDs, and mice with Ube2f deletion in colon epithelial cells are significantly more resistant to DSS-induced colitis and AOM-DSS induced colon tumorigenesis. Mechanistically, Ube2f deletion inactivates Cullin-RING ligase-5 (CRL5) E3, leading to accumulation of protein tyrosine phosphatase receptor type N (PTPRN), a new substrate of CRL5, and a stabilizer of p-STAT5, to promote differentiation of ISCs into secretory lineages for epithelial integrity against colitis, which is abrogated by a STAT5 PROTAC degrader.