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

Vignesh Srinivasan, Celine Bruelle, Enzo Scifo, Dan Duc Pham, Rabah Soliymani, Maciej Lalowski, Dan Bj Lindholm

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Abstrakti

USP14 is a deubiquitinating enzyme associated with the proteasome that is important for protein
degradation. Here we show that upon proteasomal inhibition or expression of the mutant W58A38 USP14, association of USP14 with the 19S regulatory particle is disrupted. MS-based interactomics revealed an interaction of USP14 with the chaperone, HSC70 in neuroblastoma cells. 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 downregulated
USP14. Furthermore, proteasome inhibition or the use of mutant W58A-USP14 facilitated 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 HSC70 inhibitor, VER-155008. Modulation of the USP14-HSC70 axis by
various drugs may represent a potential therapeutic target in HD to beneficially influence multiple
proteostasis pathways
Alkuperäiskielienglanti
Artikkeli100790
LehtiiScience
Vuosikerta23
Numero1
Sivumäärä33
ISSN2589-0042
DOI - pysyväislinkit
TilaJulkaistu - 24 tammikuuta 2020
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

  • 1182 Biokemia, solu- ja molekyylibiologia

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