Referenced in: none

Automatically associated channels: TRP , TRPM , TRPML , TRPML1

Title: Loss of the lysosomal ion channel TRPML1 leads to cathepsin B-dependent apoptosis.

Authors: Grace A Colletti, Mark T Miedel, James Quinn, Neel Andharia, Ora A Weisz, Kirill Kiselyov

Journal, date & volume: , 2012 Jan 18 , ,

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22262857

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.