IP6K1 interacts with the syndecan SDC4 to support secretory granule biogenesis in gastric chief cells

Inositol hexakisphosphate kinases (IP6Ks) catalyze the synthesis of the inositol pyrophosphate 5-InsP₇, and regulate diverse physiological processes. Ip6k1^-/- mice display reduced body weight despite normal food intake, elevated fecal protein, and reduced skeletal muscle mass compared with Ip6k1^+/+ mice, suggesting that IP6K1 may support protein digestion. IP6K1 is expressed throughout the mouse gastrointestinal tract, and is especially enriched in the cytoplasm of chief cells in the stomach, which are responsible for the storage and secretion of digestive enzymes. Pepsinogen C (PGC) containing granules were sparse, and gastric lipase F granules were completely absent in the gastric glands of Ip6k1^-/- mice, despite normal expression levels of these enzymes, implicating IP6K1 in digestive enzyme granule biogenesis. The level of the active protease pepsin C was decreased in the gastric lumen of Ip6k1^-/- mice compared with Ip6k1^+/+ mice. CRISPR/Cas9-mediated deletion of IP6K1 in the gastric adenocarcinoma cell line AGS recapitulated the phenotype of reduced PGC granules seen in gastric chief cells of Ip6k1^-/- mice. PGC granule formation was restored in IP6K1^-/- AGS cells by the reintroduction of catalytically active or inactive IP6K1, indicating that IP6K1 supports the formation of secretory granules independent of its enzymatic activity. The proteoglycan SDC4, identified as an interactor of IP6K1, was seen to colocalize and comigrate with PGC granules in IP6K1^+/+ but not in IP6K1^-/- AGS cells. Our findings identify IP6K1 as a novel regulator of secretory granule biogenesis in gastric chief cells, to influence protein digestion in the mammalian stomach.NEW & NOTEWORTHY Through detailed phenotypic analysis of Ip6k1^-/- mice and mechanistic studies, we identify IP6K1 as a key regulator of digestive enzyme granule biogenesis and secretion in gastric glands. IP6K1 is shown to act via its specific interactor, the proteoglycan syndecan-4 (SDC4), to mediate pepsinogen C granule biogenesis. By extending IP6K1's functional landscape into gastrointestinal biology, our study opens new avenues for understanding its impact on digestion and metabolic health.