Abstract

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.

Links

Publisher Full Text

Authors

Moscovitz O, Tsvetkov P, Hazan N, Michaelevski I, Keisar H, Ben-Nissan G, Shaul Y, Sharon M

Institution

Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.

Source

Molecular cell 47:1 2012 Jul 13 pg 76-86

MeSH

Animals
Apoenzymes
Blotting, Western
Cell Line, Tumor
Enzyme Stability
Feedback, Physiological
Flavin-Adenine Dinucleotide
HEK293 Cells
HeLa Cells
Humans
Mass Spectrometry
Models, Biological
Models, Molecular
NAD(P)H Dehydrogenase (Quinone)
Proteasome Endopeptidase Complex
Protein Binding
Protein Folding
Proteolysis
Rats
Recombinant Proteins
Temperature

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22793692