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 a-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.

Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice

“…We found that CR treatment caused a dose-dependent increase in NQO1 protein levels irrespective of sex and strain; however, the magnitude of this increase was much lower in D2 males on 40% CR (Figure 4G, Figure S3D). NQO1 also functions as a gatekeeper protein capable of competing with the 20S proteasome for interaction with different proteins (Moscovitz et al, 2015). Binding of NQO1 to the key metabolic regulator PGC-1α leads to its stabilization and protection against proteasomal degradation (Adamovich et al, 2013).…”

A Two-step Protein Quality Control Pathway for a Misfolded DJ-1 Variant in Fission Yeast

“…Interestingly, human DJ-1 was itself recently shown to regulate the activity of the 20S proteasome (66), and presumably wild type Sdj1 functions in a similar manner in fission yeast. However, as the experiments presented here were all performed in an sdj1 ϩ wild type genetic background, and Sdj1-L169P fails to interact with Sdj1, such a function of Sdj1 is unlikely to be relevant for our analyses on the degradation of misfolded Sdj1-L169P.…”

Protein misfolding in neurodegenerative diseases: implications and strategies

“…For example, many of the gene mutations that cause familial PD encode proteins involved in the UPS and/or autophagy, including PINK-1, Parkin (a ubiquitin ligase), UCH-L1 (Ub carboxy terminal hydrolase L1), DJ-1 (PARK7), and LRRK2/PRAK8 [79, 81, 82]. As with the chaperone system, choosing promising drug targets from the UPS or autophagy pathways is challenging because of the number of proteins involved (there are ~ 500 to 1000 associated just with the UPS system).…”