PERK orchestrates an endoplasmic reticulum stress alternative splicing program via CLK1/SRSF1
Abstract
The unfolded protein response (UPR) is a critical adaptive program triggered upon cellular stresses that profoundly reshapes the transcriptome and translatome. In the very first minutes of cellular stress, translation blockage, RNA decay and RNA granules formation prompt the synthesis of proteins essential to the stress response. Due to the dynamic nature of these processes, investigating translation upon stress has proven to be challenging; therefore, our understanding of these mechanisms and translatome rewiring upon stress remains limited. Here, we exploit O-Propargyl-puromycin (OPP) labelling of de novo peptides followed by LC-MS/MS to identify de novo proteins translated upon endoplasmic reticulum (ER) stress. Combined with transcriptomic analyses, our approach reveals that ER stress profoundly impacts the synthesis of core splicing factor proteins leading to a significant reshaping of the splicing landscape. We identify a signature of seven splicing events consistently occurring in mammalian cells exposed to ER stress. Using pharmacological, genetic, phosphoproteomic and sequencing approaches, we demonstrate that this specific signature is driven by PERK activation and is dependent on the axis CLK1/SRSF1. Our findings identify PERK/CLK1/SRSF1 -mediated splicing regulation as a new facet of ER stress, defining an ERi-splice signature spanning healthy and malignant tissues.
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BibTeX
@article{philippe2026perk,
title = {{PERK orchestrates an endoplasmic reticulum stress alternative splicing program via CLK1/SRSF1}},
author = {Céline Philippe and Shoshana Burke and Arantxa Carrasco-Leon and Andrea Martisova and Pedro Casado and Eleni Maniati and Jimena Castorena Rodriguez and Pantelitsa Protopapa and Ru-Pin Alicia Chi and Rachel Boniface and Vinothini Rajeeve and Martin Dodel and Beatriz Galvão and Marc Aubry and Kaliya Svetlinova Georgieva and Doriana Di Bella and Brian N. Papas and Taylor Floyd and Kendall Anderson and Martin Akerman and Jun Wang and Lovorka Stojic and Faraz Mardakheh and Marcos Morgan and Eric Chevet and Christian Touriol and Pedro R Cutillas and Kevin Rouault-Pierre},
journal = {Nature Communications},
year = {2026},
month = jun,
doi = {10.1038/s41467-026-74397-y},
url = {https://hal.science/hal-05679396v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - PERK orchestrates an endoplasmic reticulum stress alternative splicing program via CLK1/SRSF1
AU - Céline Philippe
AU - Shoshana Burke
AU - Arantxa Carrasco-Leon
AU - Andrea Martisova
AU - Pedro Casado
AU - Eleni Maniati
AU - Jimena Castorena Rodriguez
AU - Pantelitsa Protopapa
AU - Ru-Pin Alicia Chi
AU - Rachel Boniface
AU - Vinothini Rajeeve
AU - Martin Dodel
AU - Beatriz Galvão
AU - Marc Aubry
AU - Kaliya Svetlinova Georgieva
AU - Doriana Di Bella
AU - Brian N. Papas
AU - Taylor Floyd
AU - Kendall Anderson
AU - Martin Akerman
AU - Jun Wang
AU - Lovorka Stojic
AU - Faraz Mardakheh
AU - Marcos Morgan
AU - Eric Chevet
AU - Christian Touriol
AU - Pedro R Cutillas
AU - Kevin Rouault-Pierre
PY - 2026
DA - 2026/06/19
JO - Nature Communications
DO - 10.1038/s41467-026-74397-y
UR - https://hal.science/hal-05679396v1
AB - The unfolded protein response (UPR) is a critical adaptive program triggered upon cellular stresses that profoundly reshapes the transcriptome and translatome. In the very first minutes of cellular stress, translation blockage, RNA decay and RNA granules formation prompt the synthesis of proteins essential to the stress response. Due to the dynamic nature of these processes, investigating translation upon stress has proven to be challenging; therefore, our understanding of these mechanisms and translatome rewiring upon stress remains limited. Here, we exploit O-Propargyl-puromycin (OPP) labelling of de novo peptides followed by LC-MS/MS to identify de novo proteins translated upon endoplasmic reticulum (ER) stress. Combined with transcriptomic analyses, our approach reveals that ER stress profoundly impacts the synthesis of core splicing factor proteins leading to a significant reshaping of the splicing landscape. We identify a signature of seven splicing events consistently occurring in mammalian cells exposed to ER stress. Using pharmacological, genetic, phosphoproteomic and sequencing approaches, we demonstrate that this specific signature is driven by PERK activation and is dependent on the axis CLK1/SRSF1. Our findings identify PERK/CLK1/SRSF1 -mediated splicing regulation as a new facet of ER stress, defining an ERi-splice signature spanning healthy and malignant tissues.
SN - 2041-1723
SN - 2041-1723
ER -