ROS-mediated DJ-1 monomerization modulates intracellular trafficking involving Karyopherin-2

Bjørkblom, Benny, Maple-Grødem, Jodi, Puno, Marc Rhyan , Odell, Mark, Larsen, Jan Petter and Geir-Moller, Simon (2014) ROS-mediated DJ-1 monomerization modulates intracellular trafficking involving Karyopherin-2. Molecular and Cellular Biology, 34 (16). pp. 3024-3040. ISSN 0270-7306

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Mutations in DJ-1 are a cause of recessive, early-onset Parkinson's disease (PD). Although oxidative stress and mitochondrial integrity have been implicated in PD, it is largely unknown why neurons degenerate. DJ-1 is involved in oxidative stress-mediated responses and in mitochondrial maintenance; however, its specific function remains vague. Here we show that DJ-1 exhibits neuronal dynamic intracellular trafficking, with dimeric/monomeric cycling modulated by the oxidative environment. We demonstrate that oxidative stress enhances monomerization of wild-type cytosolic DJ-1, leading to nuclear recruitment. The pathogenic DJ-1/E163K variant is unable to homodimerize but is retained in the cytosol upon wild-type DJ-1 heterodimerization. We found that this wild-type/pathogenic heterodimer is disrupted by oxidative stress, leading to DJ-1/E163K mitochondrial translocation. We further demonstrated that endogenously expressed wild-type DJ-1 is imported into neuronal nuclei as a monomer and that nucleo-cytoplasmic transport is oxidative stress mediated. We identified a novel proline-tyrosine nuclear localization signal (PY-NLS) in DJ-1, and we found that nuclear monomeric DJ-1 import is mediated by an oxidative stress-dependent interaction with karyopherin β2. Our study provides evidence that oxidative stress-mediated intracellular trafficking of DJ-1, mediated by dynamic DJ-1 dimeric/monomeric cycling, is implicated in PD pathogenesis.

Keywords:DJ-1, Parkinson's disease, monomerisation, nuclear transport, karyopherin b2
Subjects:C Biological Sciences > C130 Cell Biology
C Biological Sciences > C720 Biological Chemistry
B Subjects allied to Medicine > B140 Neuroscience
C Biological Sciences > C131 Applied Cell Biology
Divisions:College of Science > School of Life Sciences
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ID Code:39024
Deposited On:02 Dec 2019 09:58

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