Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ubiquitin-proteasome system (UPS) is responsible for most selective protein degradation in eukaryotes and regulates numerous cellular processes, including cell cycle control and protein quality control. A component of this system, the deubiquitinating enzyme USP14, associates with the proteasome where it can rescue substrates from degradation by removal of the ubiquitin tag. We previously found that a small-molecule inhibitor of USP14, known as IU1, can increase the rate of degradation of a subset of proteasome substrates. We report here the synthesis and characterization of 87 variants of IU1, which resulted in the identification of a 10-fold more potent USP14 inhibitor that retains specificity for USP14. The capacity of this compound, IU1-47, to enhance protein degradation in cells was tested using as a reporter the microtubule-associated protein tau, which has been implicated in many neurodegenerative diseases. Using primary neuronal cultures, IU1-47 was found to accelerate the rate of degradation of wild-type tau, the pathological tau mutants P301L and P301S, and the A152T tau variant. We also report that a specific residue in tau, lysine 174, is critical for the IU1-47-mediated tau degradation by the proteasome. Finally, we show that IU1-47 stimulates autophagic flux in primary neurons. In summary, these findings provide a powerful research tool for investigating the complex biology of USP14.
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PMID:An inhibitor of the proteasomal deubiquitinating enzyme USP14 induces tau elimination in cultured neurons. 2897 60

The ubiquitin-proteasome system and the autophagy-lysosome system are two major intracellular proteolytic pathways in eukaryotes. Although several biochemical mechanisms underlying the crosstalk between them have been suggested, little is known about the effect of enhanced proteasome activity on autophagic flux. Here, we found that upregulation of proteasome activity, which was achieved through the inhibition of USP14, significantly impaired cellular autophagic flux, especially at the autophagosome-lysosome fusion step. UVRAG appeared to function as a crucial checkpoint for the proper progression of autophagic flux. Although proteasome activation through USP14 inhibition facilitated the clearance of microtubule-associated protein tau (MAPT) and reduced the amount of its oligomeric forms, the same conditions increased the formation of inclusion bodies from nonproteasomal substrates such as huntingtin with long polyglutamine repeats. Our results collectively indicate that USP14 may function as a common denominator in the compensatory negative feedback between the two major proteolytic processes in the cell.
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PMID:Dual Function of USP14 Deubiquitinase in Cellular Proteasomal Activity and Autophagic Flux. 3068 98

In eukaryotes, most proteins are degraded through one of the 2 major proteolytic pathways: the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Existing evidence suggests that these processes are critical to human physiology and pathology. Our study revealed a negative feedback system between proteasomal activity and autophagic flux in cells. We demonstrated that proteasome activation achieved by USP14 (ubiquitin specific peptidase 14) inhibition delays the fusion of autophagosomes with the lysosome. A new molecular circuit involving UVRAG (UV radiation resistance associated) was uncovered as a key linker between the systems, adding complexity to the regulatory crosstalk. These findings clearly demonstrate that the surveillance mechanisms for protein homeostasis and cell survival are not separate, but a coordinated system. We also found that proteasome activation promotes the clearance of MAPT (microtubule associated protein tau), while facilitating the aggregation of mutant HTT (huntingtin) in cells, indicating that the biochemical property of a protein might play a role in its response to degradation signals. Collectively, our results present novel mechanistic insights into the reciprocal communication between the UPS and autophagy, highlighting that while a strategy upregulating either the UPS or autophagy holds great potential, it may have caveats originating from the intrinsic feedback regulation between them.
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PMID:Negative-feedback coordination between proteasomal activity and autophagic flux. 3002 Nov 69