title: Loss of lysosomal ion channel transient receptor potential channel mucolipin-1 (TRPML1) leads to cathepsin B-dependent apoptosis.
abstract: Mucolipidosis type IV (MLIV) is a lysosomal storage disease caused by mutations in the gene MCOLN1, which codes for the transient receptor potential family ion channel TRPML1. MLIV has an early onset and is characterized by developmental delays, motor and cognitive deficiencies, gastric abnormalities, retinal degeneration, and corneal cloudiness. The degenerative aspects of MLIV have been attributed to cell death, whose mechanisms remain to be delineated in MLIV and in most other storage diseases. Here we report that an acute siRNA-mediated loss of TRPML1 specifically causes a leak of lysosomal protease cathepsin B (CatB) into the cytoplasm. CatB leak is associated with apoptosis, which can be prevented by CatB inhibition. Inhibition of the proapoptotic protein Bax prevents TRPML1 KD-mediated apoptosis but does not prevent cytosolic release of CatB. This is the first evidence of a mechanistic link between acute TRPML1 loss and cell death.
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Grace A
authors.initials: GA
authors.lastname: Colletti
authors.forename: Mark T
authors.initials: MT
authors.lastname: Miedel
authors.forename: James
authors.initials: J
authors.lastname: Quinn
authors.forename: Neel
authors.initials: N
authors.lastname: Andharia
authors.forename: Ora A
authors.initials: OA
authors.lastname: Weisz
authors.forename: Kirill
authors.initials: K
authors.lastname: Kiselyov
mesh_terms: D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009081:Mucolipidoses / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C494826:BAX protein, human; C416674:MCOLN1 protein, human; D050051:Transient Receptor Potential Channels; D051028:bcl-2-Associated X Protein; C533912:CTSB protein, human; D002401:Cathepsin B