Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6.
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.
Olzmann
James A
JA
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Li
Lian
L
Chudaev
Maksim V
MV
Chen
Jue
J
Perez
Francisco A
FA
Palmiter
Richard D
RD
Chin
Lih-Shen
LS
D000818:Animals; D002460:Cell Line; D004398:Dyneins / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D016631:Lewy Bodies / Q000378:metabolism; D051379:Mice; D009154:Mutation; D015513:Oncogene Proteins / Q000378:metabolism*; D015388:Organelles / Q000378:metabolism; D054464:Peroxiredoxins; D025821:Polyubiquitin / Q000378:metabolism*; D011485:Protein Binding; D000071617:Protein Deglycase DJ-1; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D025821:Polyubiquitin; D054464:Peroxiredoxins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C105131:PARK7 protein, human; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; C433811:HDAC6 protein, human; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D004398:Dyneins