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

Bjørkblom, B., Maple-Grødem, J., Puno, M.R., Odell, M., Larsen, J.P. and Møller, S. 2014. ROS-mediated DJ-1 monomerization modulates intracellular trafficking involving Karyopherin-2. Molecular and Cellular Biology. 34 (16), pp. 3024-3040.

TitleROS-mediated DJ-1 monomerization modulates intracellular trafficking involving Karyopherin-2
AuthorsBjørkblom, B., Maple-Grødem, J., Puno, M.R., Odell, M., Larsen, J.P. and Møller, S.
Abstract

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.

JournalMolecular and Cellular Biology
Journal citation34 (16), pp. 3024-3040
Year2014
Digital Object Identifier (DOI)doi:10.1128/MCB.00286-14
Publication dates09 Jun 2014

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