The Parkinson’s-associated protein DJ-1 regulates the 20S proteasome

Oren Moscovitz, Gili Ben-Nissan, Irit Fainer, Dan Pollack, Limor Mizrachi and Michal Sharon ()
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Oren Moscovitz: Weizmann Institute of Science
Gili Ben-Nissan: Weizmann Institute of Science
Irit Fainer: Weizmann Institute of Science
Dan Pollack: Weizmann Institute of Science
Limor Mizrachi: Weizmann Institute of Science
Michal Sharon: Weizmann Institute of Science

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7609

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