Dual Function of USP14 Deubiquitinase in Cellular Proteasomal Activity and Autophagic Flux

Abstract

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.

The PARK10 gene USP24 is a negative regulator of autophagy and ULK1 protein stability

“…Dysregulation of the both major protein degradation pathways, the autophagy-lysosome system and the ubiquitin proteasome system, has been linked to neurodegeneration. Although initially the two pathways were thought to work independently, recent work has revealed many layers of both positive and negative interaction [47][48][49]. This includes a number of DUBs such as USP14 that have been implicated in regulation of autophagy and coordination of autophagy and proteasomal function [49].…”

“…Although initially the two pathways were thought to work independently, recent work has revealed many layers of both positive and negative interaction [47][48][49]. This includes a number of DUBs such as USP14 that have been implicated in regulation of autophagy and coordination of autophagy and proteasomal function [49]. There is also substantial data demonstrating that ubiquitination and deubiquitination is involved in regulation of the class III PtdIns3K activity and several DUBs have been identified [35,50].…”

The central regulator p62 between ubiquitin proteasome system and autophagy and its role in the mitophagy and Parkinson's disease

“…When USP14 activity is inhibited, intracellular proteasome activity is correspondingly increased (22), whereas the autophagy flux is impeded at the step of autophagosome-lysosome fusion (22). Furthermore, treatment of cultured cells with a small chemical inhibitor of USP14, IU1, considerably inhibits the oligomerization of microtubuleassociated protein tau protein (22). In contrast, the blockage of USP14 activity significantly upregulates the level of huntingtin with 97-polyglutamine repeats (22).…”

“…Furthermore, treatment of cultured cells with a small chemical inhibitor of USP14, IU1, considerably inhibits the oligomerization of microtubuleassociated protein tau protein (22). In contrast, the blockage of USP14 activity significantly upregulates the level of huntingtin with 97-polyglutamine repeats (22). These diverse outcomes imply that the effect of USP14 inhibition largely depends on the selective cellular context and appears to be substratespecific.…”

Negative-feedback coordination between proteasomal activity and autophagic flux

“…Upregulation of the UPS or autophagy has generally been considered a promising strategy to protect cells against proteotoxic stress. To elucidate the reciprocal consequences, we examined the change in autophagic flux after proteasome activation (via USP14 inhibition), and the stability of UPS substrates after autophagy induction (via nutrient starvation) [1]. Our experiments revealed that the UPS and autophagy appear to operate under a negative feedback regulation system, with USP14 being the common denominator of the 2 proteolytic machineries.…”