TY - JOUR
T1 - The Parkinson's-associated protein DJ-1 regulates the 20S proteasome
AU - Moscovitz, Oren
AU - Ben-Nissan, Gili
AU - Mizrachi, Limor
AU - Pollack, Dan
AU - Fainer, Irit
AU - Sharon, Michal
N1 - We thank Yosef Shaul, Maya Schuldiner and Gad Asher for helpful discussions. We are grateful to Gregory Petsko, Hilal Lashuel, Assaf Friedler, Chaim Kahana and Yosef Shaul for providing antibodies, plasmids and cells. We are thankful for the financial support of a Starting Grant from the European Research Council (ERC) (Horizon 2020)/ERC Grant Agreement no. 636752, an Acceleration Grant from the Israel Cancer Research Foundation, as well as the Minerva Foundation, with funding from the Federal Ministry for Education and Research, Germany and the Abisch-Frenkel Foundation, Switzerland. M.S. is the incumbent of the Elaine Blond Career Development Chair. O.M., G.B.-N. and M.S. designed the experiments and analysed the data. O.M., G.B.-N., I.F., D.P. and L.M. performed the experiments. M.S. wrote the manuscript.
PY - 2015/4/2
Y1 - 2015/4/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84926328165&partnerID=8YFLogxK
U2 - 10.1038/ncomms7609
DO - 10.1038/ncomms7609
M3 - مقالة
SN - 2041-1723
VL - 6
JO - Nature Communications
JF - Nature Communications
M1 - 6609
ER -