title: The Parkinson's-associated protein DJ-1 regulates the 20S proteasome.
abstract: The Parkinson's-associated protein, DJ-1, is a highly conserved homodimer, ubiquitously expressed in cells. Here we demonstrate that DJ-1 is a 20S proteasome regulator. We show that DJ-1 physically binds the 20S proteasome and inhibits its activity, rescuing partially unfolded proteins from degradation. Consequently, DJ-1 stabilizes the cellular levels of 20S proteasome substrates, as we show for α-synuclein and p53. Furthermore, we demonstrate that following oxidative stress, DJ-1 is involved in the Nrf2-dependent oxidative stress response that leads to the upregulation of both the 20S proteasome and its regulator, NQO1. Overall, our results suggest a regulatory circuit in which DJ-1, under conditions of oxidative stress, both upregulates and inhibits the 20S proteasome, providing a rigorous control mechanism at a time when the 20S proteasome becomes the major proteolytic machinery. Such a tight regulation of the 20S proteasome may sustain the balance between the need to rapidly eliminate oxidatively damaged proteins and maintain the abundance of native, intrinsically unstructured proteins, which coordinate regulatory and signalling events.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Oren
authors.initials: O
authors.lastname: Moscovitz
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Gili
authors.initials: G
authors.lastname: Ben-Nissan
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Fainer
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Pollack
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Limor
authors.initials: L
authors.lastname: Mizrachi
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Sharon
mesh_terms: D000818:Animals; D002460:Cell Line; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D018384:Oxidative Stress; D054464:Peroxiredoxins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D000071617:Protein Deglycase DJ-1; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D051267:NF-E2-Related Factor 2; D015513:Oncogene Proteins; D054464:Peroxiredoxins; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C491732:Nqo1 protein, mouse; C105131:PARK7 protein, human; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease