PI3Kα signalling contributes to lysosome repopulation via INPP4B

About the talk: INPP4B suppresses PI3K/AKT signalling by converting PI(3,4)P 2 to PI(3)P and we recently demonstrated INPP4B facilitates class PI3Kα crosstalk with Wnt signalling in ER+ve breast cancer on late endosomes. We observed in these studies that the conversion ofPI(3,4)P 2 to PI(3)P on late endosomes by INPP4B, was associated an increase in the number of late endosomes and lysosomes, dependent on INPP4B catalytic phosphatase activity. It is known that the repopulation of lysosomes is essential for many cellular functions such as the degradation of intracellular components and recycling nutrients during autophagy. Here, we investigated whether INPP4B contributed to autophagy by facilitating the repopulation of lysosomes. We show that Class I PI3Kα-derived PI(3)P generated by INPP4B on late endosomes is essential for basal, but not starvation-induced autophagic degradation. PI(3)Psignals were maintained on late endosomes as they matured into endolysosomes, and served as the substrate for the 5-kinase, PIKfyve, to generate PI(3,5)P 2. Under nutrient-rich conditions, PI3Kα, INPP4B and PIKfyve sequentially contributed to basal autophagic degradation and protection from proteotoxic stress via PI(3,5)P 2 -dependent lysosome reformation from endolysosomes. These findings reveal that endosome maturation couplesClass I PI3Kα signalling to lysosome reformation during basal autophagy.