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DJ-1 (PARK7) associates with lipid rafts

Kim, Kwang-Soo; Kim, Jin Su; Jou, Ilo; Joe, Eun-hye; Park, Sang Myun
Department of Pharmacology, Ajou University School of Medicine
Parkinson’s disease (PD) is a neurodegenerative disorder caused by cell death of dopaminergic neuron. Among PD-related genetic factors, loss-of-function DJ-1 mutants cause recessively inherited PD. DJ-1 is a multifunctional protein with anti-oxidant, chaperone and transcriptional activity. Previous reports demonstrated that the localization of DJ-1 in cytoplasm, mitochondria and nucleus is recognized, however the relevance of this sub-cellular compartmentalization to its neuroprotective or functional activity is not completely understood. In this study, we explored whether endogenous DJ-1 is localized to lipid raft on the plasma membrane or not. We showed that approximately 10% of endogenous DJ- 1 exists to detergent-resistant insoluble or lipid raft fraction. Its localization was significantly inhibited by 2-bromopalmitate, a palmitoylation inhibitor. Also, the overexpression DJ-1 mutant with Ala substitution of all three Cys residues (C46A/C53A/C106A), whose residues of DJ-1 may be targets for palmitoylation fails to associate with detergent-resistant insoluble and lipid raft fraction. These results suggest that DJ-1 undergoes palmitoylation, a post-translational modification, which is considerably responsible for targeting to lipid raft. However, PD-associated pathological mutants (M26I, E64D and L166P) and its dimerization do not affect to the subcellular distribution of DJ-1 in similar to wild type DJ-1. In addition, we showed that DJ-1 localization on the lipid raft requires precisely the C-terminal region of DJ-1. Furthermore, the translocation of DJ-1 to lipid raft is significantly increased by TLR4-mediated LPS signal. Taken together, these results imply that DJ-1 might be translocated to modulate the lipid raft-associated signaling pathway via palmitoylation.
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