Class I p110alpha-PI3Ks crosstalk with nutrient sensing mTOR signalling regulates stress and injury responses in the intestinal epithelium
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Phospoinositide-3-kinases (PI3Ks) are evolutionarily conserved lipid kinases that regulate essential organismal pathways for cell growth, division, proliferation, and are often deregulated in cancer and inflammation. PI3Ks regulate innate immune responses through detection of microbes via pathogen recognition receptors (PRRs)1. The oncogenic p110α-PI3K isoform is highly associated with several cancers and overgrowth diseases2. Nutrient sensing of amino acids (AAs), contributes to cell growth and proliferation involving PI3K-activation of the mammalian target of rapamycin (mTOR), known to regulate intestinal epithelial cells (IECs) regenerative activities3,4. NOD1/2 are cytosolic PPRs which detect D-amino-dipeptides from the bacterial-cell-wall component peptidoglycan and regulate stem cell renewal and wound healing in the intestine5. However, how p110α-PI3K regulates functions downstream PRR-signalling pathways in IECs is not well understood. Since, mutations in NOD2 have been associated with and increased risk of inflammatory bowel disease (IBD)6–8, I hypothesized that NOD1/2-mediated activation of the p110α-mTOR axis, by intracellular detection of D-amino dipeptides, may be essential for initiating protective cellular responses to injury in IECs. Herein, by genetic and pharmacological targeting in vivo and in vitro, I established that NOD1/2 triggering by bacterial D-amino-dipeptides selectively couple to p110α, which activate AKT/mTOR pathways. Strikingly, temporal inactivation of p110α-RBD interaction in adult mice results in partial lethality following DSS-intestinal injury, due to defects in IEC repair and function, which can be comparably reproduced in mouse with IEC-intrinsic Rheb deletion or lacking NOD1/NOD2. Critically, I demonstrated in vitro that under AA low conditions, eukaryotic AA-sensing mTORC1 pathway requires p110α-RBD by extracellular protein uptake to sense intracellular D-amino dipeptides, analogous to NOD pathway. These results establish for the first time that the p110α-RBD interaction mediates activation of mTOR by uptake of bacterial-peptides and couples to the intestinal repair and function, adding a new layer to the complexity of symbiotic host-microbiome interactions.
Authors
Laura Medrano, GonzálezCollections
- Theses [4203]