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GSK-3-TSC axis governs lysosomal acidification through autophagy and endocytic pathways

机译：GSK-3-TSC轴通过自噬和内吞的途径治理溶酶体酸化

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Impaired lysosomal activity, which results in defective protein processing, waste accumulation, and protein aggregation, is implicated in a number of disease pathologies. Acidification of lysosomes is a crucial process required for lysosome function. Previously we showed that inhibition of glycogen synthase kinase-3 (GSK-3) enhanced lysosomal acidification in both normal and pathological conditions. However, how GSK-3 integrates into the lysosome networking is unknown. Here we show that inhibition of mTORC1 and increased autophagic activity are downstream to GSK-3 inhibition and contribute to lysosomal acidification. Strikingly, lysosomal acidification is also restored by GSK-3 inhibition in the absence of functional autophagy, and, independently of mTORC1. This is facilitated by increased endocytic traffic: We show that GSK-3 inhibition enhanced material internalization, increased recruitment of active Rab5 into endosomes, and increased Rab7/RILP clustering into lysosomes, all processes required for late endosome maturation. Consistently, in cells defective in endocytic traffic caused by either constitutively active Rab5, or, deletion of the Niemann-Pick C1 protein, GSK-3 inhibition could not restore lysosomal acidification. Finally we found that the tuberous sclerosis complex, TSC, is required for lysosomal acidification and is activated by GSK-3 inhibition. Thus, the GSK-3/TSC axis regulates lysosomal acidification via both the autophagic and endocytic pathways. Our study provides new insights into the therapeutic potential of GSK-3 inhibitors in treating pathological conditions associated with impaired cellular clearance.
机译：溶酶体活性受损，导致蛋白质加工，废物积累和蛋白质聚集有缺陷，涉及许多疾病病理。溶酶体的酸化是溶酶体功能所需的关键方法。以前，我们表明抑制糖原合酶激酶-3（GSK-3）在正常和病理条件下增强了溶酶体酸化。但是，GSK-3如何集成到溶质网络中是未知的。在这里，我们表明MTORC1的抑制和增加的自噬活性是GSK-3抑制的下游，并有助于溶酶体酸化。尖锐的是，在没有功能性自噬的情况下，通过GSK-3抑制还恢复溶酶体酸化，并且独立于MTORC1。通过增加的内肾上流量来促进这一点：我们表明GSK-3抑制增强的材料内化，将活性RAB5的募集增加进入内体，并将RAB7 / RILP聚合物升高到溶酶体中，所有过程患者所需的所有方法。一致地，在细胞中，通过组成型活性RAB5引起的内肾上腺交通缺陷，或缺失Niemann-PICK C1蛋白，GSK-3抑制不能恢复溶酶体酸化。最后，我们发现溶酶体酸化需要结节硬化综合体，TSC，并通过GSK-3抑制激活。因此，GSK-3 / TSC轴通过自噬和内吞径来调节溶酶体酸化。我们的研究为GSK-3抑制剂的治疗潜力提供了新的见解，治疗与细胞间隙受损相关的病理病理病理条件。

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