The RNA-binding protein Imp1 promotes a Spdef transcriptional program and mucus fucosylation during necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is the most deadly gastrointestinal disease in preterm neonates, with up to 50% mortality. There is no cure for NEC. Enhancing our understanding of intestinal epithelial cell (IEC) responses to NEC will provide novel therapeutic targets. The RNA-binding protein insulin-like growth factor 2 mRNA binding protein 1 (IMP1) plays roles in intestinal development and repair. Notably, roles for IMP1 in NEC are unknown. Intestinal goblet cells produce protective mucus, and their function depends on the transcription factor Spdef. Evidence suggests that goblet cell mucus glycosylation affects barrier function and inflammation. We aimed to define the role of IMP1 in NEC damage response using neonatal human enteroids and a NEC-like intestinal injury model. At post-natal day 3, wild-type mice or littermates with IEC-specific Imp1 overexpression ( Imp1 IEC-OE ) or loss ( Imp1 ∆IEC ) were assigned to control or NEC groups. NEC was induced with stress, formula feeding, bacterial exposure, and hypoxia. Imp1 effects on NEC response were assessed using RNA sequencing, western blotting, immunostaining, and a cytokine array. We found that pro-inflammatory bacteria induced IMP1 expression in neonatal human enteroids. During NEC, Imp1 IEC-OE mice exhibit more severe intestinal damage and priming for lytic cell death. Elevated Imp1 levels were linked to a Spdef transcriptional signature and in silico analysis predicted Imp1 binding to Spdef and mucus glycosylation mediator mRNAs. Functionally, Imp1 increased fucosylation in the intestinal epithelium. Collectively, results suggest that Imp1 primes the intestine for lytic death and promotes the production of fucosylated mucus, changes which could alter the damage response.