title: Homeostatic regulation of the proteasome via an Rpn4-dependent feedback circuit.
abstract: The 26S proteasome is a complex protease consisting of at least 32 different subunits. Early studies showed that Rpn4 (also named Son1 and Ufd5) is a transcriptional activator of the Saccharomyces cerevisiae proteasome genes, and that Rpn4 is rapidly degraded by the 26S proteasome. These observations suggested that in vivo proteasome abundance may be regulated by an Rpn4-dependent feedback circuit. Here, we present direct evidence to support the Rpn4-proteasome feedback model. We show that proteasome expression is increased when proteasome activity is impaired, and that this increase is Rpn4-dependent. Moreover, we demonstrate that expression of a stable form of Rpn4 leads to elevation of proteasome expression. Our data also reveal that the Rpn4-proteasome feedback circuit is critical for cell growth when proteasome activity is compromised, and plays an important role in response to DNA damage. This study provides important insights into the mechanism underlying proteasome homeostasis.
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Department of Pathology, Wayne State University School of Medicine, 110 Warren Avenue, Detroit, MI 48201, USA.
authors.forename: Donghong
authors.initials: D
authors.lastname: Ju
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Xicheng
authors.initials: X
authors.lastname: Mao
authors.forename: Youming
authors.initials: Y
authors.lastname: Xie
mesh_terms: D004268:DNA-Binding Proteins / Q000378:metabolism*; D005246:Feedback; D005838:Genotype; D007700:Kinetics; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D016335:Zinc Fingers
chemical_list: D004268:DNA-Binding Proteins; D021122:Protein Subunits; C119430:RPN4 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease