title: Lysosomal thiol reductase negatively regulates autophagy by altering glutathione synthesis and oxidation.
abstract: Redox regulation is critical for a number of cellular functions and has been implicated in the etiology and progression of several diseases, such as cardiovascular diseases, neurodegenerative diseases, and cancer. It has been shown that, in the absence of gamma-interferon inducible lysosomal thiol reductase (GILT), cells are under increased oxidative stress with higher superoxide levels and decreased stability, expression, and function of mitochondrial manganese superoxide dismutase (SOD2). Here, we further elucidate the role of GILT in the homeostatic regulation of oxidative stress. We show that GILT-deficient fibroblasts exhibit reduced glutathione levels, shift in GSSG/GSH ratio toward the oxidized form, and accumulate dysfunctional mitochondria. Redox-sensitive pathways involving Erk1/2 activation and nuclear high mobility group box 1 (HMGB1) protein cytosolic translocation are both activated and associated with increased autophagy in GILT-/- fibroblasts. We hypothesize that these events are responsible for degrading the damaged mitochondria and mitochondrial SOD2 in the absence of GILT. This is the first time to our knowledge that a lysosomal enzyme has been implicated in global effects within the cell.
authors.affiliation: Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Hao-Sen
authors.initials: HS
authors.lastname: Chiang
authors.forename: Maja
authors.initials: M
authors.lastname: Maric
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D002461:Cell Line, Transformed; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005978:Glutathione / Q000378:metabolism*; D024243:HMGB1 Protein / Q000378:metabolism; D006706:Homeostasis; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D050862:Oxidoreductases Acting on Sulfur Group Donors; D015398:Signal Transduction / Q000235:genetics
chemical_list: D024243:HMGB1 Protein; D010088:Oxidoreductases; C483811:Ifi30 protein, mouse; D050862:Oxidoreductases Acting on Sulfur Group Donors; D048052:Mitogen-Activated Protein Kinase 3; D005978:Glutathione