Apoptosis caused by cathepsins does not require Bid signaling in an in vivo model of progressive myoclonus epilepsy (EPM1).
Apoptosis can be mediated by mechanisms other than the traditional caspase-mediated cleavage cascade. There is growing recognition that alternative proteolytic enzymes such as the lysosomal cathepsin proteases can initiate or propagate proapoptotic signals, but it is currently unclear how cathepsins achieve these actions. Recent in vitro evidence suggests that cathepsins cleave the proapoptotic Bcl-2 family member Bid, thereby activating it and allowing it to induce the mitochondrial release of cytochrome c and subsequent apoptosis. We have tested this hypothesis in vivo by breeding mice that lack cathepsin inhibition (cystatin B-deficient mice) to Bid-deficient mice, to determine whether the apoptosis caused by cathepsins is dependent on Bid signaling. We found that cathepsins are still able to promote apoptosis even in the absence of Bid, indicating that these proteases mediate apoptosis via a different pathway, or that some other molecule can functionally substitute for Bid in this system.
Houseweart
M K
MK
Department of Genetics, School of Medicine, Stanford University, 300 Pasteur Drive, Stanford, CA 94305-5120, USA.
Vilaythong
A
A
Yin
X-M
XM
Turk
B
B
Noebels
J L
JL
Myers
R M
RM
D000367:Age Factors; D000818:Animals; D017209:Apoptosis; D001259:Ataxia; D051023:BH3 Interacting Domain Death Agonist Protein; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D002403:Cathepsins / Q000378:metabolism*; D016923:Cell Death; D002531:Cerebellum / Q000378:metabolism; D055313:Cystatin B; D015891:Cystatins / Q000235:genetics; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D004569:Electroencephalography; D005838:Genotype; D020287:In Situ Nick-End Labeling; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D020191:Myoclonic Epilepsies, Progressive / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D002352:Carrier Proteins; C524992:Cstb protein, mouse; D015891:Cystatins; D019253:Proto-Oncogene Proteins c-bcl-2; D055313:Cystatin B; D045304:Cytochromes c; D002403:Cathepsins