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Dynamic Interaction of USP14 with the Chaperone HSC70 Mediates Crosstalk between Proteaseome, ER Signaling and Autophagy

2019; RELX Group (Netherlands); Linguagem: Inglês

10.2139/ssrn.3441912

1556-5068

Vignesh Srinivasan, Céline Bruelle, Enzo Scifo, Dan Duc Pham, Rabah Soliymani, Maciej Łałowski, Dan Lindholm,

Ubiquitin and proteasome pathways

USP14 is a deubiquitinating enzyme associated with the proteasome, important for protein degradation. Here we show that upon proteasomal inhibition, or expressing the mutant W58A-USP14, the association of USP14 with the 19S regulatory particle is disrupted. MS-based interactomics revealed an interaction of USP14 with the chaperone, HSC70. Proteasome inhibition enhanced binding of USP14 to HSC70, but also to XBP1u and IRE1α proteins, demonstrating a role in the unfolded protein response. Striatal neurons expressing mutant huntingtin exhibited reduced USP14 and HSC70 levels, whilst inhibition of HSC70 lowered USP14. Proteasome inhibition or use of W58A-USP14 facilitated also the interaction of USP14 with the autophagy protein, GABARAP. Functionally, overexpression of W58A-USP14 increased GABARAP positive autophagosomes in striatal neurons, and this was abrogated using the chemical compound VER-155008 to inhibit HSC70. Modulation of the USP14-HSC70 axis by various drugs may represent a potential therapeutic target in HD to beneficially influence multiple proteostasis pathways.