PMID:19597489

Citation	Siepe, D and Jentsch, S (2009) Prolyl isomerase Pin1 acts as a switch to control the degree of substrate ubiquitylation. Nat. Cell Biol. 11:967-72
Abstract	Pin1, a conserved eukaryotic peptidyl-prolyl cis/trans isomerase, has important roles in cellular regulation. Because of its activity to switch the conformation of peptidyl-proline bonds in polypeptide chains, Pin1 operates as a binary switch, often in fate-determining pathways. Pin1 activity is usually controlled by substrate phosphorylation, but how Pin1 switches protein fates has been unclear. Here we show that Pin1 controls the degree of substrate ubiquitylation and thereby protein functions. We found that yeast Pin1 (Ess1) is essential for viability because it controls the NF-kappaB-related Spt23 transcription factor involved in unsaturated fatty-acid synthesis. High Pin1 activity results in low ubiquitylation of Spt23, which triggers Spt23 precursor processing and hence transcription factor activation. By contrast, decreased Pin1 activity leads to robust Spt23 polyubiquitylation and subsequent proteasomal degradation. Inhibition of Pin1 in mammalian cells changes the ubiquitylation status of the tumour suppressor protein p53 from oligoubiquitylation, which is known to trigger nuclear export, to polyubiquitylation, which causes nuclear p53 degradation. This suggests that the Pin1 activity is often translated into a fate-determining ubiquitylation switch, and that Pin1 may affect the degree of substrate ubiquitylation in other pathways as well.
Links	PubMed Online version:10.1038/ncb1908
Keywords	Active Transport, Cell Nucleus/drug effects; Cell Line, Tumor; Cell Nucleus/metabolism; Enzyme Inhibitors/pharmacology; Humans; Immunoblotting; Immunoprecipitation; Leupeptins/pharmacology; Membrane Proteins; Microscopy, Fluorescence; Naphthoquinones/pharmacology; Peptidylprolyl Isomerase/antagonists & inhibitors; Peptidylprolyl Isomerase/genetics; Peptidylprolyl Isomerase/metabolism; Phosphorylation; Proteasome Endopeptidase Complex/antagonists & inhibitors; Proteasome Endopeptidase Complex/metabolism; Protein Binding; Saccharomyces cerevisiae Proteins/genetics; Saccharomyces cerevisiae Proteins/metabolism; Substrate Specificity; Trans-Activators/genetics; Trans-Activators/metabolism; Transcription Factors; Tumor Suppressor Protein p53/metabolism; Ubiquitin/genetics; Ubiquitin/metabolism; Ubiquitination
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
YEAST:ESS1	involved_in	GO:2000059: negative regulation of ubiquitin-dependent protein catabolic process	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

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