Lysosomal protease deficiency or substrate overload induces an oxidative-stress mediated STAT3-dependent pathway of lysosomal homeostasis
Lysosomal protease deficiency or substrate overload induces an oxidative-stress mediated STAT3-dependent pathway of lysosomal homeostasis
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DOI：
10.1038/s41467-018-07741-6
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发表时间：
2018-12-17
影响因子：
16.6
通讯作者：
Watts, Colin
中科院分区：
文献类型：
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作者：
Martinez-Fabregas, Jonathan;Prescott, Alan;Watts, Colin
多种细胞过程依赖于溶酶体蛋白酶系统，但细胞如何调节溶酶体蛋白水解能力仅部分了解。我们在此表明，细胞可以通过多种溶酶体水解酶的从头表达来对该区室中的蛋白酶/底物不平衡做出反应。这种反应，例如天冬酰胺内肽酶 (AEP) 或其他溶酶体半胱氨酸蛋白酶的丧失，或内吞底物负载的增加，不依赖于转录因子 EB (TFEB)，而是由溶酶体氧化应激下游的 STAT3 激活触发。在表达 STAT3 组成型活性形式的小鼠和细胞中也观察到类似的溶酶体适应。我们的结果揭示了细胞如何在“进食”而非“饥饿”条件下增加溶酶体蛋白酶能力，从而激活 TFEB 系统。此外，溶酶体应激引起的 STAT3 激活可能解释了在 AEP 缺陷小鼠中观察到的过度增殖性肾病和脾肿大。
Diverse cellular processes depend on the lysosomal protease system but how cells regulate lysosomal proteolytic capacity is only partly understood. We show here that cells can respond to protease/substrate imbalance in this compartment by de novo expression of multiple lysosomal hydrolases. This response, exemplified here either by loss of asparagine endopeptidase (AEP) or other lysosomal cysteine proteases, or by increased endocytic substrate load, is not dependent on the transcription factor EB (TFEB) but rather is triggered by STAT3 activation downstream of lysosomal oxidative stress. Similar lysosomal adaptations are seen in mice and cells expressing a constitutively active form of STAT3. Our results reveal how cells can increase lysosomal protease capacity under 'fed' rather than 'starved' conditions that activate the TFEB system. In addition, STAT3 activation due to lysosomal stress likely explains the hyperproliferative kidney disease and splenomegaly observed in AEP-deficient mice.