ArticleProceedings of the National Academy of Sciences of the United States of America2020
cGMP via PKG activates 26S proteasomes and enhances degradation of proteins, including ones that cause neurodegenerative diseases.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 97 citations in OpenAlex.
- Stimulating proteasomal degradation in human proteinopathies.The FEBS journal · 2026Review
- α-Synuclein blocks endoplasmic reticulum co-translational protein translocation early in Parkinson's disease.Nature communications · 2026Article
- Influence of Exercise on Proteolysis-Related Markers of Cardiac, Renal, and Endothelial Dysfunction.Cureus · 2026Article
- Regulation via compartmentation: adaptive localization of the proteasome under stress.Biochemical Society transactions · 2025Review
- Early proteasome downregulation and dysfunction drive proteostasis failure in Alzheimer's disease.Brain : a journal of neurology · 2025Article
- Proteomic and metabolomic profiling nominates druggable targets and biomarkers for pulmonary arterial hypertension-associated myopathy and exercise intolerance in male monocrotaline rats.The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation · 2025Article
- UBQLN2 in neurodegenerative disease: mechanistic insights and emerging therapeutic potential.Biochemical Society transactions · 2025Review
- Article
- Carbonic anhydrase inhibition ameliorates tau toxicity via enhanced tau secretion.Nature chemical biology · 2025Article
- Promoting proteostasis by cAMP/PKA and cGMP/PKG.Trends in molecular medicine · 2025Review
- E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.The EMBO journal · 2025Article
- Activators of the 26S proteasome when protein degradation increases.Experimental & molecular medicine · 2025Review
- Activation of the 26S Proteasome to Reduce Proteotoxic Stress and Improve the Efficacy of PROTACs.ACS pharmacology & translational science · 2025Review
- Proteasome: Role in T Cell Function Regulation.International journal of biological sciences · 2025Review
- Understanding neurodevelopmental proteasomopathies as new rare disease entities: A review of current concepts, molecular biomarkers, and perspectives.Genes & diseases · 2024Review
- The Emerging Role of Phosphodiesterase 5 Inhibition in Neurological Disorders: The State of the Art.Cells · 2024Review
- Pharmacologically increasing cGMP improves proteostasis and reduces neuropathy in mouse models of CMT1.Cellular and molecular life sciences : CMLS · 2024Article
- Maximum entropy determination of mammalian proteome dynamics.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- GUCY2C signaling limits dopaminergic neuron vulnerability to toxic insults.NPJ Parkinson's disease · 2024Article
- Knockout of PA200 improves proteasomal degradation and myelination in a proteotoxic neuropathy.Life science alliance · 2024Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Because raising cAMP enhances 26S proteasome activity and the degradation of cell proteins, including the selective breakdown of misfolded proteins, we investigated whether agents that raise cGMP may also regulate protein degradation. Treating various cell lines with inhibitors of phosphodiesterase 5 or stimulators of soluble guanylyl cyclase rapidly enhanced multiple proteasome activities and cellular levels of ubiquitinated proteins by activating protein kinase G (PKG). PKG stimulated purified 26S proteasomes by phosphorylating a different 26S component than is modified by protein kinase A. In cells and cell extracts, raising cGMP also enhanced within minutes ubiquitin conjugation to cell proteins. Raising cGMP, like raising cAMP, stimulated the degradation of short-lived cell proteins, but unlike cAMP, also markedly increased proteasomal degradation of long-lived proteins (the bulk of cell proteins) without affecting lysosomal proteolysis. We also tested if raising cGMP, like cAMP, can promote the degradation of mutant proteins that cause neurodegenerative diseases. Treating zebrafish models of tauopathies or Huntington's disease with a PDE5 inhibitor reduced the levels of the mutant huntingtin and tau proteins, cell death, and the resulting morphological abnormalities. Thus, PKG rapidly activates cytosolic proteasomes, protein ubiquitination, and overall protein degradation, and agents that raise cGMP may help combat the progression of neurodegenerative diseases.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.