Deficiency in class III PI3-kinase confers postnatal lethality with IBD-like features in zebrafish.

The class III PI3-kinase (PIK3C3) is an enzyme responsible for the generation of phosphatidylinositol 3-phosphate (PI3P), a critical component of vesicular membrane. Here, we report that PIK3C3 deficiency in zebrafish results in intestinal injury and inflammation. In pik3c3 mutants, gut tube forms but fails to be maintained. Gene expression analysis reveals that barrier-function-related inflammatory bowel disease (IBD) susceptibility genes (e-cadherin, hnf4a, ttc7a) are suppressed, while inflammatory response genes are stimulated in the mutants. Histological analysis shows neutrophil infiltration into mutant intestinal epithelium and the clearance of gut microbiota. Yet, gut microorganisms appear dispensable as mutants cultured under germ-free condition have similar intestinal defects. Mechanistically, we show that PIK3C3 deficiency suppresses the formation of PI3P and disrupts the polarized distribution of cell-junction proteins in intestinal epithelial cells. These results not only reveal a role of PIK3C3 in gut homeostasis, but also provide a zebrafish IBD model.

Antidepressant-like effect of valproic acid-Possible involvement of PI3K/Akt/mTOR pathway.

RATIONALE: Few studies suggest that antidepressants exert their effects by activating some signaling pathways, including the phosphatidylinositol 3-kinase (PI3K). Moreover, valproic acid (VPA) activates the PI3K pathway. Thus, here we investigated the antidepressant-like effect of VPA and if its effect is related to PI3K/Akt/mTOR activation. METHODS: C57Bl/6 (WT) and PI3Kγ-/- mice received VPA injections (30, 100 or 300mg/kg, i.p.) and 30min after they were submitted to the forced swimming (FS), tail suspension (TS) and open field (OF) tests. Another group was pretreated with rapamycin (5mg/kg, i.p.) 150min before VPA administration. Akt phosphorylation levels were measured by Western blotting. RESULTS: In WT mice, VPA (30mg/kg) reduced the immobility time in both FS and TS tests. However, VPA (300mg/kg) increased the immobility time in FS test. All doses of VPA did not alter locomotor activity. In PI3Kγ-/- mice, none of the doses revealed antidepressant-like effect. However, in the OF test, the lower dose of VPA increased the travelled distance in comparison with vehicle group. An increase in Akt phosphorylation levels was observed in WT, but not in PI3Kγ-/- mice. Finally, the pretreatment of WT mice with rapamycin abolished the antidepressant-like effect of VPA (30mg/kg) in FS test. CONCLUSION: These data suggest that the antidepressant-like effects of VPA might depend on PI3K and mTOR activation. Thus, more studies are necessary to investigate the mechanisms involved in the antidepressant-like effect induced by VPA in order to investigate novel therapeutic targets for the treatment of depression.

BRD7 regulates XBP1s' activity and glucose homeostasis through its interaction with the regulatory subunits of PI3K.

Bromodomain-containing protein 7 (BRD7) is a member of the bromodomain-containing protein family that is known to play a role as tumor suppressors. Here, we show that BRD7 is a component of the unfolded protein response (UPR) signaling through its ability to regulate X-box binding protein 1 (XBP1) nuclear translocation. BRD7 interacts with the regulatory subunits of phosphatidylinositol 3-kinase (PI3K) and increases the nuclear translocation of both p85α and p85ß and the spliced form of XBP1 (XBP1s). Deficiency of BRD7 blocks the nuclear translocation of XBP1s. Furthermore, our in vivo studies have shown that BRD7 protein levels are reduced in the liver of obese mice, and reinstating BRD7 levels in the liver restores XBP1s nuclear translocation, improves glucose homeostasis, and ultimately reduces the blood glucose levels in the obese and diabetic mouse models.

Altered macrophage function contributes to colitis in mice defective in the phosphoinositide-3 kinase subunit p110δ.

BACKGROUND & AIMS: Innate immune responses are crucial for host defense against pathogens but need to be tightly regulated to prevent chronic inflammation. Initial characterization of mice with a targeted inactivating mutation in the p110δ subunit of phosphoinositide 3-kinase (PI3K p110δ(D910A/D910A)) revealed defects in B- and T-cell signaling and chronic colitis. Here, we further characterize features of inflammatory bowel diseases in these mice and investigate underlying innate immune defects. METHODS: Colons and macrophages from PI3K p110δ(D910A/D910A) mice were evaluated for colonic inflammation and innate immune dysfunction. Colonic p110δ messenger RNA expression was examined in interleukin (IL)-10(-/-) and wild-type germ-free mice during transition to a conventional microbiota. To assess polygenic impact on development of colitis, p110δ(D910A/D910A) mice were backcrossed to IL-10(-/-) mice. RESULTS: A mild spontaneous colitis was shown in PI3K p110δ(D910A/D910A) mice at 8 weeks, with inflammation increasing with age. An inflammatory mucosal and systemic cytokine profile was characterized by expression of IL-12/23. In PI3K p110δ(D910A/D910A) macrophages, augmented toll-like receptor signaling and defective bactericidal activity were observed. Consistent with an important homeostatic role for PI3K p110δ, wild-type mice raised in a germ-free environment markedly up-regulated colonic PI3K p110δ expression with the introduction of the enteric microbiota; however, colitis-prone IL-10(-/-) mice did not. Moreover, PI3K p110δ(D910A/D910A) mice crossed to IL-10(-/-) mice developed severe colitis at an early age. CONCLUSIONS: This study describes a novel model of experimental colitis that highlights the importance of PI3K p110δ in maintaining mucosal homeostasis and could provide insight into the pathogenesis of human inflammatory bowel disease.