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Published online September 10, 2007
doi:10.1083/jcb.200611128
The Journal of Cell Biology, Vol. 178, No. 6, 1025-1038
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Olzmann et al.
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Article

 Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6

James A. Olzmann1, Lian Li1, Maksim V. Chudaev1, Jue Chen1, Francisco A. Perez2, Richard D. Palmiter2, and Lih-Shen Chin1

1 Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322
2 Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195

Correspondence to Lih-Shen Chin: chinl{at}pharm.emory.edu

Sequestration of misfolded proteins into pericentriolar inclusions called aggresomes is a means that cells use to minimize misfolded protein-induced cytotoxicity. However, the molecular mechanism by which misfolded proteins are recruited to aggresomes remains unclear. Mutations in the E3 ligase parkin cause autosomal recessive Parkinson's disease that is devoid of Lewy bodies, which are similar to aggresomes. Here, we report that parkin cooperates with heterodimeric E2 enzyme UbcH13/Uev1a to mediate K63-linked polyubiquitination of misfolded DJ-1. K63-linked polyubiquitination of misfolded DJ-1 serves as a signal for interaction with histone deacetylase 6, an adaptor protein that binds the dynein–dynactin complex. Through this interaction, misfolded DJ-1 is linked to the dynein motor and transported to aggresomes. Furthermore, fibroblasts lacking parkin display deficits in targeting misfolded DJ-1 to aggresomes. Our findings reveal a signaling role for K63-linked polyubiquitination in dynein-mediated transport, identify parkin as a key regulator in the recruitment of misfolded DJ-1 to aggresomes, and have important implications regarding the biogenesis of Lewy bodies.

Abbreviations used in this paper: HA, hemagglutinin; HDAC6, histone deacetylase 6; MDC, monodansyl cadaverine; MEF, mouse embryonic fibroblast; PD, Parkinson's disease.


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