title: Sub-lethal oxidative stress induces lysosome biogenesis via a lysosomal membrane permeabilization-cathepsin-caspase 3-transcription factor EB-dependent pathway.
abstract: Here we provide evidence to link sub-lethal oxidative stress to lysosome biogenesis. Exposure of cells to sub-lethal concentrations of exogenously added hydrogen peroxide resulted in cytosol to nuclear translocation of the Transcription Factor EB (TFEB), the master controller of lysosome biogenesis and function. Nuclear translocation of TFEB was dependent upon the activation of a cathepsin-caspase 3 signaling pathway, downstream of lysosomal membrane permeabilization and accompanied by a significant increase in lysosome numbers as well as induction of TFEB-dependent lysosome-associated genes expression such as Ctsl, Lamp2 and its spliced variant Lamp2a, Neu1and Ctsb and Sqstm1 and Atg9b. The effects of sub-lethal oxidative stress on lysosomal gene expression and biogenesis were rescued upon gene silencing of caspase 3 and TFEB. Notably, caspase 3 activation was not associated with phenotypic hallmarks of apoptosis, evidenced by the absence of caspase 3 substrate cleavage, such as PARP, Lamin A/C or gelsolin. Taken together, these data demonstrate for the first time an unexpected and non-canonical role of a cathepsin-caspase 3 axis in the nuclear translocation of TFEB leading to lysosome biogenesis under conditions of sub-lethal oxidative stress.
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.|National University of Singapore Graduate School for Integrative Sciences and Engineering, Singapore, Singapore.
authors.forename: San Min
authors.initials: SM
authors.lastname: Leow
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Shu Xian Serene
authors.initials: SX
authors.lastname: Chua
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.|National University of Singapore Graduate School for Integrative Sciences and Engineering, Singapore, Singapore.
authors.forename: Gireedhar
authors.initials: G
authors.lastname: Venkatachalam
authors.affiliation: Biostatistic Unit, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Liang
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Le
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.|National University of Singapore Graduate School for Integrative Sciences and Engineering, Singapore, Singapore.
authors.forename: Marie-Veronique
authors.initials: MV
authors.lastname: Clement
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015151:Immunoblotting; D007425:Intracellular Membranes / Q000378:metabolism; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D034622:RNA Interference; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D016877:Oxidants; C574124:TFEB protein, rat; D006861:Hydrogen Peroxide; D002403:Cathepsins; D053148:Caspase 3
keywords: Autophagy; caspase 3; lysosomal membrane permeabilization; lysosomes; sub-lethal oxidative stress; transcription factor EB