L166P mutant DJ-1 promotes cell death by dissociating Bax from mitochondrial Bcl-XL.
BACKGROUND
Mutations or deletions in DJ-1/PARK7 gene are causative for recessive forms of early onset Parkinson's disease (PD). Wild-type DJ-1 has cytoprotective roles against cell death through multiple pathways. The most commonly studied mutant DJ-1(L166P) shifts its subcellular distribution to mitochondria and renders cells more susceptible to cell death under stress stimuli. We previously reported that wild-type DJ-1 binds to Bcl-XL and stabilizes it against ultraviolet B (UVB) irradiation-induced rapid degradation. However, the mechanisms by which mitochondrial DJ-1(L166P) promotes cell death under death stimuli are largely unknown.


RESULTS
We show that DJ-1(L166P) is more prone to localize in mitochondria and it binds to Bcl-XL more strongly than wild-type DJ-1. In addition, UVB irradiation significantly promotes DJ-1(L166P) translocation to mitochondria and binding to Bcl-XL. DJ-1(L166P) but not wild-type DJ-1 dissociates Bax from Bcl-XL, thereby leading to Bax enrichment at outer mitochondrial membrane and promoting mitochondrial apoptosis pathway in response to UVB irradiation.


CONCLUSIONS
Our findings suggest that wild-type DJ-1 protects cells and DJ-1(L166P) impairs cells by differentially regulating mitochondrial Bax/Bcl-XL functions.
Department of Pharmacology, Laboratory of Molecular Neuropathology, Soochow University College of Pharmaceutical Sciences, Suzhou, Jiangsu 215123, People's Republic of China.
Haigang
H
Ren
Kai
K
Fu
Chenchen
C
Mu
Xuechu
X
Zhen
Guanghui
G
Wang
D016923:Cell Death / Q000502:physiology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D000071617:Protein Deglycase DJ-1; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
C494826:BAX protein, human; C494811:BCL2L1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1