Transnitrosylation from DJ-1 to PTEN attenuates neuronal cell death in parkinson's disease models.
Emerging evidence suggests that oxidative/nitrosative stress, as occurs during aging, contributes to the pathogenesis of Parkinson's disease (PD). In contrast, detoxification of reactive oxygen species and reactive nitrogen species can protect neurons. DJ-1 has been identified as one of several recessively inherited genes whose mutation can cause familial PD, and inactivation of DJ-1 renders neurons more susceptible to oxidative stress and cell death. DJ-1 is also known to regulate the activity of the phosphatase and tensin homolog (PTEN), which plays a critical role in neuronal cell death in response to various insults. However, mechanistic details delineating how DJ-1 regulates PTEN activity remain unknown. Here, we report that PTEN phosphatase activity is inhibited via a transnitrosylation reaction [i.e., transfer of a nitric oxide (NO) group from the cysteine residue of one protein to another]. Specifically, we show that DJ-1 is S-nitrosylated (forming SNO-DJ-1); subsequently, the NO group is transferred from DJ-1 to PTEN by transnitrosylation. Moreover, we detect SNO-PTEN in human brains with sporadic PD. Using x-ray crystallography and site-directed mutagenesis, we find that Cys106 is the site of S-nitrosylation on DJ-1 and that mutation of this site inhibits transnitrosylation to PTEN. Importantly, S-nitrosylation of PTEN decreases its phosphatase activity, thus promoting cell survival. These findings provide mechanistic insight into the neuroprotective role of SNO-DJ-1 by elucidating how DJ-1 detoxifies NO via transnitrosylation to PTEN. Dysfunctional DJ-1, which lacks this transnitrosylation activity due to mutation or prior oxidation (e.g., sulfonation) of the critical cysteine thiol, could thus contribute to neurodegenerative disorders like PD.
Neuroscience and Aging Research Center.
Min Sik
MS
Choi
Neuroscience and Aging Research Center.
Tomohiro
T
Nakamura
Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037.
Seung-Je
SJ
Cho
Department of Chemical Physiology and Department of Molecular and Cellular Neurobiology, The Scripps Research Institute, La Jolla, California 92037, and.
Xuemei
X
Han
Neuroscience and Aging Research Center.
Emily A
EA
Holland
Neuroscience and Aging Research Center.
Jing
J
Qu
Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10065.
Gregory A
GA
Petsko
Department of Chemical Physiology and Department of Molecular and Cellular Neurobiology, The Scripps Research Institute, La Jolla, California 92037, and.
John R
JR
Yates
Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037.
Robert C
RC
Liddington
Neuroscience and Aging Research Center, slipton@sanfordburnham.org.
Stuart A
SA
Lipton
D000368:Aged; D000369:Aged, 80 and over; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D017209:Apoptosis; D016022:Case-Control Studies; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D015513:Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D000071617:Protein Deglycase DJ-1
D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D009569:Nitric Oxide; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
DJ-1; PTEN; Parkinson's disease; S-nitrosylation; nitric oxide; transnitrosylation