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Suppression of lysosome function induces autophagy via a feedback down-regulation of MTOR complex 1 (MTORC1) activity

机译:溶酶体功能的抑制通过MTOR复合物1(MTORC1)活性的反馈下调诱导自噬。

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摘要

Autophagy can be activated via MTORC1 down-regulation by amino acid deprivation and by certain chemicals such as rapamycin, torin, and niclosamide. Lysosome is the degrading machine for autophagy but has also been linked to MTORC1 activation through the Rag/RRAG GTPase pathway. This association raises the question of whether lysosome can be involved in the initiation of autophagy. Toward this end, we found that niclosamide, an MTORC1 inhibitor, was able to inhibit lysosome degradation and increase lysosomal permeability. Niclosamide was ineffective in inhibiting MTORC1 in cells expressing constitutively activated Rag proteins, suggesting that its inhibitory effects were targeted to the Rag-MTORC1 signaling system. This places niclosamide in the same category of bafilomycin A1 and concanamycin A, inhibitors of the vacuolar H(+)-ATPase, for its dependence on Rag GTPase in suppression of MTORC1. Surprisingly, classical lysosome inhibitors such as chloroquine, E64D, and pepstatin A were also able to inhibit MTORC1 in a Rag-dependent manner. These lysosome inhibitors were able to activate early autophagy events represented by ATG16L1 and ATG12 puncta formation. Our work established a link between the functional status of the lysosome in general to the Rag-MTORC1 signaling axis and autophagy activation. Thus, the lysosome is not only required for autophagic degradation but also affects autophagy activation. Lysosome inhibitors can have a dual effect in suppressing autophagy degradation and in initiating autophagy.
机译:自噬可以通过MTORC1下调(通过氨基酸剥夺)和某些化学物质(例如雷帕霉素,甲苯胺和烟酰胺)来激活。溶酶体是自噬的降解机器,但也已通过Rag / RRAG GTPase途径与MTORC1激活相关。这种关联提出了溶酶体是否可以参与自噬启动的问题。为此,我们发现烟酰胺(一种MTORC1抑制剂)能够抑制溶酶体降解并增加溶酶体通透性。 Niclosamide在表达组成型激活的Rag蛋白的细胞中不能有效抑制MTORC1,这表明其抑制作用针对于Rag-MTORC1信号系统。由于其依赖于Rag GTPase抑制MTORC1,因此将新药置于类空泡液H(+)-ATPase的抑制剂bafilomycin A1和conconanamycin A的同一类别中。令人惊讶的是,经典的溶酶体抑制剂,例如氯喹,E64D和胃抑素A也能够以Rag依赖性方式抑制MTORC1。这些溶酶体抑制剂能够激活以ATG16L1和ATG12点形成为代表的早期自噬事件。我们的工作在溶酶体的功能状态(通常与Rag-MTORC1信号转导轴之间)与自噬激活之间建立了联系。因此,溶酶体不仅是自噬降解所必需的,而且还影响自噬的活化。溶酶体抑制剂可在抑制自噬降解和启动自噬方面具有双重作用。

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