Autophagy depends on the repopulation of lysosomes to degrade intracellular components and recycle nutrients. How cells co-ordinate lysosome repopulation during basal autophagy, which occurs constitutively under nutrient-rich conditions, is unknown. Here, we identify an endosome-dependent phosphoinositide pathway that links PI3Kα signaling to lysosome repopulation during basal autophagy. We show that PI3Kα-derived PI(3)P generated by INPP4B on late endosomes was required for basal but not starvation-induced autophagic degradation. PI(3)P signals were maintained as late endosomes matured into endolysosomes, and served as the substrate for the 5-kinase, PIKfyve, to generate PI(3,5)P₂. The SNX-BAR protein, SNX2, was recruited to endolysosomes by PI(3,5)P₂ and promoted lysosome reformation. Inhibition of INPP4B/PIKfyve-dependent lysosome reformation reduced autophagic clearance of protein aggregates during proteotoxic stress leading to increased cytotoxicity. Therefore under nutrient-rich conditions, PI3Kα, INPP4B, and PIKfyve sequentially contribute to basal autophagic degradation and protection from proteotoxic stress via PI(3,5)P₂-dependent lysosome reformation from endolysosomes. These findings reveal that endosome maturation couples PI3Kα signaling to lysosome reformation during basal autophagy.

中文翻译：

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内体成熟将 PI3Kα 信号传导与基础自噬过程中的溶酶体再增殖联系起来

自噬依赖于溶酶体的再增殖以降解细胞内成分并回收营养。在营养丰富的条件下组成性发生的基础自噬过程中，细胞如何协调溶酶体再增殖尚不清楚。在这里，我们确定了一种依赖内体的磷酸肌醇途径，该途径将 PI3Kα 信号传导与基础自噬过程中的溶酶体再增殖联系起来。我们表明，由 INPP4B 在晚期内体上产生的 PI3Kα 衍生的 PI(3)P 是基础而非饥饿诱导的自噬降解所必需的。当晚期内体成熟为内溶酶体时，PI(3)P 信号得以维持，并作为 5-激酶 PIKfyve 的底物，以产生 PI(3,5)P ₂。SNX-BAR 蛋白 SNX2 被 PI(3,5)P _{2招募到内溶酶体}并促进溶酶体改造。抑制 INPP4B/PIKfyve 依赖的溶酶体重组可降低蛋白毒性应激期间蛋白质聚集体的自噬清除，从而导致细胞毒性增加。因此，在营养丰富的条件下，PI3Kα、INPP4B 和 PIKfyve 通过 PI(3,5)P ₂依赖的溶酶体从内溶酶体重组，依次促进基础自噬降解和保护免受蛋白毒性应激。这些发现表明，在基础自噬过程中，内体成熟将 PI3Kα 信号传导与溶酶体重组相结合。