TY - JOUR
T1 - A Mutually Inhibitory Feedback Loop between the 20S Proteasome and Its Regulator, NQO1
AU - Moscovitz, Oren
AU - Tsvetkov, Peter
AU - Hazan, Nimrod
AU - Michaelevski, Izhak
AU - Keisar, Hodaya
AU - Ben-Nissan, Gili
AU - Shaul, Yosef
AU - Sharon, Michal
N1 - Funding Information:
The authors thank Maya Schuldiner, Uri Alon, and Dan Tawfik, Weizmann Institute of Science, for helpful discussions, and the Sharon group members for their contributions to the research. We thank Alla Shainskaya and Tevie Mehlman (Mass Spectrometry Unit, Weizmann Institute of Science) for the proteomic analyses. M.S. is grateful for the support of the Chais Family Fellows Program for New Scientists; the Abraham and Sonia Rochlin Foundation; the Wolfson Family Charitable Trust; the estate of Shlomo and Sabine Beirzwinsky; and Miel de Botton Aynsley. M.S. is the incumbent of the Elaine Blond Career Development Chair.
PY - 2012/7/13
Y1 - 2012/7/13
N2 - NAD(P)H:quinone-oxidoreductase-1 (NQO1) is a cytosolic enzyme that catalyzes the reduction of various quinones using flavin adenine dinucleotide (FAD) as a cofactor. NQO1 has been also shown to rescue proteins containing intrinsically unstructured domains, such as p53 and p73, from degradation by the 20S proteasome through an unknown mechanism. Here, we studied the nature of interaction between NQO1 and the 20S proteasome. Our study revealed a double negative feedback loop between NQO1 and the 20S proteasome, whereby NQO1 prevents the proteolytic activity of the 20S proteasome and the 20S proteasome degrades the apo form of NQO1. Furthermore, we demonstrate, both in vivo and in vitro., that NQO1 levels are highly dependent on FAD concentration. These observations suggest a link between 20S proteolysis and the metabolic cellular state. More generally, the results may represent a regulatory mechanism by which associated cofactors dictate the stability of proteins, thus coordinating protein levels with the metabolic status.
AB - NAD(P)H:quinone-oxidoreductase-1 (NQO1) is a cytosolic enzyme that catalyzes the reduction of various quinones using flavin adenine dinucleotide (FAD) as a cofactor. NQO1 has been also shown to rescue proteins containing intrinsically unstructured domains, such as p53 and p73, from degradation by the 20S proteasome through an unknown mechanism. Here, we studied the nature of interaction between NQO1 and the 20S proteasome. Our study revealed a double negative feedback loop between NQO1 and the 20S proteasome, whereby NQO1 prevents the proteolytic activity of the 20S proteasome and the 20S proteasome degrades the apo form of NQO1. Furthermore, we demonstrate, both in vivo and in vitro., that NQO1 levels are highly dependent on FAD concentration. These observations suggest a link between 20S proteolysis and the metabolic cellular state. More generally, the results may represent a regulatory mechanism by which associated cofactors dictate the stability of proteins, thus coordinating protein levels with the metabolic status.
UR - http://www.scopus.com/inward/record.url?scp=84863816082&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2012.05.049
DO - 10.1016/j.molcel.2012.05.049
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C2 - 22793692
AN - SCOPUS:84863816082
SN - 1097-2765
VL - 47
SP - 76
EP - 86
JO - Molecular Cell
JF - Molecular Cell
IS - 1
ER -