RT Journal Article
T1 Hydroxyurea induces an oxidative stress response that triggers ER expansion and cytoplasmic protein aggregation.
A1 Sánchez Molina, Ana
A1 Bernal, M.
A1 Posligua-García, J. D.
A1 Pérez-Pulido, Antonio J.
A1 de Cubas, L.
A1 Hidalgo, E.
A1 Valdivieso, M. H.
A1 Salas-Pino, Silvia
A1 Daga, Rafael
K1 Diamide
K1 ERAD
K1 Glutathione
K1 Heat shock proteins
K1 Hydroxyurea
K1 Reactive oxygen species
K1 Ribonucleotide reductase
K1 Unfolded Protein Response
AB The endoplasmic reticulum (ER) lumen provides the proper redox environment for disulfide bond formation, which is essential for the correct folding of proteins entering the secretory pathway and forming membranes. However, the precise mechanisms by which disruptions in protein folding within the ER activate proteostatic mechanisms remain to be fully elucidated. In this study, we demonstrate that in Schizosaccharomyces pombe the antineoplastic agent hydroxyurea (HU) induces a transient perinuclear ER expansion, Bip1 accumulation, and the clustering of nuclear pore complexes in a specific region of the nuclear envelope. This striking phenotype is mimicked by diamide (DIA), a specific inducer of thiol stress, and can be prevented or rapidly reversed by dithiothreitol, a reducing agent, suggesting that ER expansion results from disulfide stress. Furthermore, HU or DIA treatments resulted in the accumulation of misfolded proteins in cytoplasmic foci containing Hsp104 disaggregase and Hsp70/Ssa1 chaperones. Our data show that HU impacts redox-dependent protein folding, impairs the secretory pathway, and activates specific proteostatic mechanisms in both the ER and the cytoplasm
PB PlOS
YR 2025
FD 2025-11-19
LK https://hdl.handle.net/10433/25197
UL https://hdl.handle.net/10433/25197
LA en
NO PLoS Biol. 2025 Nov 19;23(11):e3003493
NO Proyectos de investigaciónMICIU/AEI/10.13039/501100011033/FEDER (UE) grants PID2021-128408OB-I00 and PID2024-160582OB-I00
NO Departamento de Biología Molecular e Ingeniería Bioquímica. Centro Andaluz de Biología del Desarrollo
DS RIO
RD May 6, 2026