Suppression of Lysosome Function Induces Autophagy via a Feedback Down-regulation of MTOR Complex 1 (MTORC1) Activity
Suppression of Lysosome Function Induces Autophagy via a Feedback Down-regulation of MTOR Complex 1 (MTORC1) Activity
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DOI：
10.1074/jbc.m113.511212
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发表时间：
2013-12-13
影响因子：
4.8
通讯作者：
Yin, Xiao-Ming
中科院分区：
文献类型：
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作者：
Li, Min;Khambu, Bilon;Yin, Xiao-Ming
背景：自噬降解需要溶酶体，而溶酶体抑制剂可以抑制自噬降解。结果：溶酶体功能的抑制通过下调MTORC 1导致自噬激活。结论：溶酶体除了参与自噬的降解外，还能影响自噬的启动。重要性：这一发现扩展了溶酶体的功能，包括自噬激活的调节，并表明溶酶体抑制剂在自噬中的双重作用。自噬可以通过氨基酸剥夺和某些化学物质如雷帕霉素、托林和氯硝柳胺通过MTORC 1下调来激活。溶酶体是自噬的降解机器，但也通过Rag/RRAG GT3途径与MTORC 1激活有关。这种关联提出了一个问题，即溶酶体是否可以参与自噬的启动。为此，我们发现，氯硝柳胺，MTORC 1抑制剂，能够抑制溶酶体降解和增加溶酶体渗透性。氯硝柳胺在抑制表达组成性激活的Rag蛋白的细胞中的MTORC 1方面无效，表明其抑制作用针对Rag-MTORC 1信号传导系统。这将氯硝柳胺与巴弗洛霉素A（1）和康卡霉素A（空泡H+-ATP酶抑制剂）归为一类，因为其在抑制MTORC 1时依赖于Rag GT3。令人惊讶的是，经典的溶酶体抑制剂如氯喹、E64 D和胃酶抑素A也能够以Rag依赖性方式抑制MTORC 1。这些溶酶体抑制剂能够激活以ATG 16 L1和ATG 12斑点形成为代表的早期自噬事件。我们的工作建立了溶酶体功能状态与Rag-MTORC 1信号轴和自噬激活之间的联系。因此，溶酶体不仅是自噬降解所必需的，而且还影响自噬激活。溶酶体抑制剂可以在抑制自噬降解和启动自噬方面具有双重作用。
Background: Lysosomes are required for autophagic degradation, which can be suppressed by lysosome inhibitors. Results: Inhibition of lysosome function resulted in autophagy activation via down-regulation of MTORC1. Conclusion: Lysosomes can affect autophagy initiation in addition to its role in autophagy degradation. Significance: The finding expands lysosome function to include regulation of autophagy activation and indicates a dual effect of lysosome inhibitors in autophagy.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 A(1) 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.