title: Calpain 1 induce lysosomal permeabilization by cleavage of lysosomal associated membrane protein 2.
abstract: In light induced retinal degeneration (LIRD) photoreceptor cell death is mediated by caspase independent mechanisms. The activation of LEI/L-DNase II pathway in this model, is due to cathepsin D release from lysosomes, although the underlying mechanism remains poorly understood. In this paper we studied the involvement of calpains in lysosomal permeabilization. We investigated, for the first time, the calpain targets at lysosomal membrane level. We found that calpain 1 is responsible for lysosomal permeabilization by cleavage of the lysosomal associated membrane protein 2 (LAMP 2). Moreover, LAMP 2 degradation and lysosomal permeabilization were rescued by calpain inhibition and the use of MEF(-/-)lamp 2 cells indicates that the cleavage of LAMP 2A is essential for this permeabilization. Finally, we found that LAMP 2 is cleaved in LIRD, suggesting that the mechanism of calpain induced lysosomal permeabilization is not exclusive of a single cell death model. Overall, these data shed new light on understanding the mechanisms of lysosomal and caspase-independent cell death and point to the original targets for development of the new therapeutic protocols.
authors.affiliation: INSERM U872 Eq. 17, Centre de Recherches des Cordeliers, Paris, France.
authors.forename: Gloria E
authors.initials: GE
authors.lastname: Villalpando Rodriguez
authors.forename: Alicia
authors.initials: A
authors.lastname: Torriglia
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D002463:Cell Membrane Permeability; D049109:Cell Proliferation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D052119:Lysosomal-Associated Membrane Protein 2 / Q000502:physiology*; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D012160:Retina / Q000166:cytology / Q000378:metabolism*
chemical_list: D052119:Lysosomal-Associated Membrane Protein 2; D002154:Calpain
keywords: AIF; ALLN; AP; Alkaline Phosphatase; Apoptosis Inducing Factor; BCA; BSA; Bicinchoninic Acid; Bovine Serum Albumin; CA; CAD; CMA; Calpain; Caspase Activated DNase; Cathepsin D; Cornu Ammonis; DMEM; Dulbecco’s Modified Eagle Medium; Endonuclease; HNE; L-DNase II; LAMP 2; LC3; LDH; LEI; LEI-derived DNase II; LIRD; Lactate dehydrogenase; Leukocyte Elastase Inhibitor; Light Chain 3; Light Induced Retinal Degeneration; Lysosomal Associated Membrane Protein 2; Lysosome; MEF; MTT; Mouse Embryonic Fibroblasts; N-Acetyl-Leu-Leu-Nle-CHO; NCCD; Nomenclature Committee of Cell Death; PBS; Phosphate-Buffered Saline; Protease; TUNEL; Terminal transferase dUTP Nick End Labeling; Thiazolil Blue Tetrazolium Bromide; WB; Western Blot; chaperon mediated autophagy; hydroxynonenal