title: Proteasome function is regulated by cyclic AMP-dependent protein kinase through phosphorylation of Rpt6.
abstract: Dysregulation of the proteasome has been documented in a variety of human diseases such as Alzheimer, muscle atrophy, cataracts etc. Proteolytic activity of 26 S proteasome is ATP- and ubiquitin-dependent. O-GlcNAcylation of Rpt2, one of the AAA ATPases in the 19 S regulatory cap, shuts off the proteasome through the inhibition of ATPase activity. Thus, through control of the flux of glucose into O-GlcNAc, the function of the proteasome is coupled to glucose metabolism. In the present study we found another metabolic control of the proteasome via cAMP-dependent protein kinase (PKA). Contrary to O-Glc-NAcylation, PKA activated proteasomes both in vitro and in vivo in association with the phosphorylation at Ser(120) of another AAA ATPase subunit, Rpt6. Mutation of Ser(120) to Ala blocked proteasome function. The stimulatory effect of PKA and the phosphorylation of Rpt6 were reversible by protein phosphatase 1 gamma. Thus, hormones using the PKA system can also regulate proteasomes often in concert with glucose metabolism. This finding might lead to novel strategies for the treatment of proteasome-related diseases.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Alabama, Birmingham, Alabama 35294, USA.
authors.forename: Fengxue
authors.initials: F
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Hu
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Toleman
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Paterson
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Kudlow
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D060588:LIM Domain Proteins; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D054645:Protein Phosphatase 1; D051381:Rats; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007546:Isoquinolines; D060588:LIM Domain Proteins; C092282:PSMC5 protein, human; D016329:Sp1 Transcription Factor; D013449:Sulfonamides; D014157:Transcription Factors; D000242:Cyclic AMP; D005982:Glutathione Transferase; D017868:Cyclic AMP-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D000074183:ATPases Associated with Diverse Cellular Activities; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide