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<p>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 ER<sup>i-splice</sup> signature spanning healthy and malignant tissues.</p>

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PERK orchestrates an endoplasmic reticulum stress alternative splicing program via CLK1/SRSF1

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月19日

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  • Céline Philippe,
  • Shoshana Burke,
  • Arantxa Carrasco-Leon,
  • Andrea Martisova,
  • Pedro Casado,
  • Eleni Maniati,
  • Jimena Castorena,
  • Pantelitsa Protopapa,
  • Alyssa Fronk,
  • Ru-Pin Alicia Chi,
  • Rachel Boniface,
  • Vinothini Rajeeve,
  • Martin Dodel,
  • Beatriz Galvão,
  • Marc Aubry,
  • Kaliya Svetlinova Georgieva,
  • Doriana Di Bella,
  • Brian N. Papas,
  • Taylor Floyd,
  • Kendall Anderson,
  • Martin Akerman,
  • Jun Wang,
  • Lovorka Stojic,
  • Faraz Mardakheh,
  • Marcos Morgan,
  • Eric Chevet,
  • Christian Touriol,
  • Pedro R. Cutillas,
  • Kevin Rouault-Pierre

摘要

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.