Cell Reports
Volume 24, Issue 3, 17 July 2018, Pages 732-743
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Article
Dual Function of USP14 Deubiquitinase in Cellular Proteasomal Activity and Autophagic Flux

https://doi.org/10.1016/j.celrep.2018.06.058Get rights and content
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Highlights

  • Inactivation of USP14 results in downregulation of autophagic flux

  • USP14 inhibition accelerates UVRAG degradation

  • Inhibition of USP14 enhances proteasomal degradation of tau/MAPT

  • USP14 is a common denominator of UPS and autophagy

Summary

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.

Keywords

USP14
proteasome
ubiquitin-proteasome system
autophagy
autophagic flux
negative feedback
UVRAG
proteostasis
tau
huntingtin

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These authors contributed equally

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