Dynamic interaction of USP14 with the chaperone HSC70 mediates crosstalk between proteasome, ER signaling and autophagy

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

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Kuvaus

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
LehtiiScience
Vuosikerta23
Numero1
ISSN2589-0042
DOI - pysyväislinkit
TilaJulkaistu - 24 tammikuuta 2020
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

  • 1182 Biokemia, solu- ja molekyylibiologia

Lainaa tätä

@article{d482d5b8854948bf8969266bd4b97f21,
title = "Dynamic interaction of USP14 with the chaperone HSC70 mediates crosstalk between proteasome, ER signaling and autophagy",
abstract = "USP14 is a deubiquitinating enzyme associated with the proteasome that is important for proteindegradation. 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 downregulatedUSP14. Furthermore, proteasome inhibition or the use of mutant W58A-USP14 facilitated the interaction of USP14 with the autophagy protein, GABARAP. Functionally, overexpression ofW58A-USP14 increased GABARAP positive autophagosomes in striatal neurons and this wasabrogated using the HSC70 inhibitor, VER-155008. Modulation of the USP14-HSC70 axis byvarious drugs may represent a potential therapeutic target in HD to beneficially influence multipleproteostasis pathways",
keywords = "1182 Biochemistry, cell and molecular biology, USP14, HSC70, autophagy, ER stress, proteasome, Huntington's disease",
author = "Vignesh Srinivasan and Celine Bruelle and Enzo Scifo and Pham, {Dan Duc} and Rabah Soliymani and Maciej Lalowski and Lindholm, {Dan Bj}",
year = "2020",
month = "1",
day = "24",
doi = "10.1016/j.isci.2019.100790",
language = "English",
volume = "23",
journal = "iScience",
issn = "2589-0042",
publisher = "Cell Press Elsevier Inc.",
number = "1",

}

Dynamic interaction of USP14 with the chaperone HSC70 mediates crosstalk between proteasome, ER signaling and autophagy. / Srinivasan, Vignesh; Bruelle, Celine; Scifo, Enzo; Pham, Dan Duc; Soliymani, Rabah; Lalowski, Maciej; Lindholm, Dan Bj.

julkaisussa: iScience, Vuosikerta 23, Nro 1, 24.01.2020.

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

TY - JOUR

T1 - Dynamic interaction of USP14 with the chaperone HSC70 mediates crosstalk between proteasome, ER signaling and autophagy

AU - Srinivasan, Vignesh

AU - Bruelle, Celine

AU - Scifo, Enzo

AU - Pham, Dan Duc

AU - Soliymani, Rabah

AU - Lalowski, Maciej

AU - Lindholm, Dan Bj

PY - 2020/1/24

Y1 - 2020/1/24

N2 - USP14 is a deubiquitinating enzyme associated with the proteasome that is important for proteindegradation. 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 downregulatedUSP14. Furthermore, proteasome inhibition or the use of mutant W58A-USP14 facilitated the interaction of USP14 with the autophagy protein, GABARAP. Functionally, overexpression ofW58A-USP14 increased GABARAP positive autophagosomes in striatal neurons and this wasabrogated using the HSC70 inhibitor, VER-155008. Modulation of the USP14-HSC70 axis byvarious drugs may represent a potential therapeutic target in HD to beneficially influence multipleproteostasis pathways

AB - USP14 is a deubiquitinating enzyme associated with the proteasome that is important for proteindegradation. 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 downregulatedUSP14. Furthermore, proteasome inhibition or the use of mutant W58A-USP14 facilitated the interaction of USP14 with the autophagy protein, GABARAP. Functionally, overexpression ofW58A-USP14 increased GABARAP positive autophagosomes in striatal neurons and this wasabrogated using the HSC70 inhibitor, VER-155008. Modulation of the USP14-HSC70 axis byvarious drugs may represent a potential therapeutic target in HD to beneficially influence multipleproteostasis pathways

KW - 1182 Biochemistry, cell and molecular biology

KW - USP14

KW - HSC70

KW - autophagy

KW - ER stress

KW - proteasome

KW - Huntington's disease

U2 - 10.1016/j.isci.2019.100790

DO - 10.1016/j.isci.2019.100790

M3 - Article

VL - 23

JO - iScience

JF - iScience

SN - 2589-0042

IS - 1

ER -