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Lysosomal protease deficiency or substrate overload induces an oxidative-stress mediated STAT3-dependent pathway of lysosomal homeostasis.

ABSTRACT: 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.

SUBMITTER: Martinez-Fabregas J

PROVIDER: S-EPMC6297226 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Lysosomal protease deficiency or substrate overload induces an oxidative-stress mediated STAT3-dependent pathway of lysosomal homeostasis.

Martínez-Fábregas Jonathan J Prescott Alan A van Kasteren Sander S Pedrioli Deena Leslie DL McLean Irwin I Moles Anna A Reinheckel Thomas T Poli Valeria V Watts Colin C

Nature communications 20181217 1

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 E ...[more]

PMID: 30559339

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Project description:Oxidative stress has been shown to induce cell death in a wide range of human diseases including cardiac ischemia/reperfusion injury, drug induced cardiotoxicity, and heart failure. However, the mechanism of cell death induced by oxidative stress remains incompletely understood. Here we provide new evidence that oxidative stress primarily induces ferroptosis, but not apoptosis, necroptosis, or mitochondria-mediated necrosis, in cardiomyocytes. Intriguingly, oxidative stress induced by organic oxidants such as tert-butyl hydroperoxide (tBHP) and cumene hydroperoxide (CHP), but not hydrogen peroxide (H2O2), promoted glutathione depletion and glutathione peroxidase 4 (GPX4) degradation in cardiomyocytes, leading to increased lipid peroxidation. Moreover, elevated oxidative stress is also linked to labile iron overload through downregulation of the transcription suppressor BTB and CNC homology 1 (Bach1), upregulation of heme oxygenase 1 (HO-1) expression, and enhanced iron release via heme degradation. Strikingly, oxidative stress also promoted HO-1 translocation to mitochondria, leading to mitochondrial iron overload and lipid reactive oxygen species (ROS) accumulation. Targeted inhibition of mitochondrial iron overload or ROS accumulation, by overexpressing mitochondrial ferritin (FTMT) or mitochondrial catalase (mCAT), respectively, markedly inhibited oxidative stress-induced ferroptosis. The levels of mitochondrial iron and lipid peroxides were also markedly increased in cardiomyocytes subjected to simulated ischemia and reperfusion (sI/R) or the chemotherapeutic agent doxorubicin (DOX). Overexpressing FTMT or mCAT effectively prevented cardiomyocyte death induced by sI/R or DOX. Taken together, oxidative stress induced by organic oxidants but not H2O2 primarily triggers ferroptotic cell death in cardiomyocyte through GPX4 and Bach1/HO-1 dependent mechanisms. Our results also reveal mitochondrial iron overload via HO-1 mitochondrial translocation as a key mechanism as well as a potential molecular target for oxidative stress-induced ferroptosis in cardiomyocytes.

Dataset Information

Lysosomal protease deficiency or substrate overload induces an oxidative-stress mediated STAT3-dependent pathway of lysosomal homeostasis.

Publications

Lysosomal protease deficiency or substrate overload induces an oxidative-stress mediated STAT3-dependent pathway of lysosomal homeostasis.

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