PERK/ATF3-dependent induction of GDE4 modulates intracellular lysophospholipid-PPARα/γ signaling

Abstract

Lysophosphatidic acid (LPA) is widely recognized as an extracellular lipid mediator; however, the functional significance of intracellularly produced LPA remains poorly understood. Here, we investigated the regulatory mechanism and functional role of a LPA-producing lysophospholipase D GDE4, also known as GDPD1, in prostate cancer cells. GDE4 expression is induced under ER stress conditions in a PERK-dependent manner and requires the transcription factor ATF3. Disruption of GDE4 expression resulted in altered intracellular levels of LPA and LPA precursor lysophosphatidylethanolamine, accompanied by reduced cell proliferation. RNA sequencing and subsequent validation identified a set of genes downregulated in GDE4-depleted cells. Pharmacological inhibition experiments indicated that peroxisome proliferator-activated receptor and {gamma} (PPAR and PPAR{gamma}) signaling pathways contribute to the regulation of these GDE4-dependent genes. Collectively, our findings suggest that GDE4-dependent lipid remodeling is associated with PPAR/{gamma}-mediated transcriptional regulation under ER stress conditions. These results provide a potential framework for understanding the link between intracellular lipid metabolism and stress-responsive gene regulation.

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BibTeX RIS

BibTeX

@misc{kitakaze2026perkatf3dependent,
  title = {{PERK/ATF3-dependent induction of GDE4 modulates intracellular lysophospholipid-PPARα/γ signaling}},
  author = {K. Kitakaze and R. Misumi and S. Nagai and H. Ali and Y. Ukai and D. Takamine and N. Takehara and Y. Iiboshi and R. Miyoshi and Y. Ito and Y. Sunada and Y. Takenouchi and K. Tsuboi and T. Tanaka and Y. Okamoto},
  howpublished = {bioRxiv},
  year = {2026},
  month = aug,
  doi = {10.64898/2026.08.27.747495},
  url = {https://www.biorxiv.org/content/10.64898/2026.08.27.747495v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - PERK/ATF3-dependent induction of GDE4 modulates intracellular lysophospholipid-PPARα/γ signaling
AU  - K. Kitakaze
AU  - R. Misumi
AU  - S. Nagai
AU  - H. Ali
AU  - Y. Ukai
AU  - D. Takamine
AU  - N. Takehara
AU  - Y. Iiboshi
AU  - R. Miyoshi
AU  - Y. Ito
AU  - Y. Sunada
AU  - Y. Takenouchi
AU  - K. Tsuboi
AU  - T. Tanaka
AU  - Y. Okamoto
PY  - 2026
DA  - 2026/08/27
PB  - bioRxiv
DO  - 10.64898/2026.08.27.747495
UR  - https://www.biorxiv.org/content/10.64898/2026.08.27.747495v1
AB  - Lysophosphatidic acid (LPA) is widely recognized as an extracellular lipid mediator; however, the functional significance of intracellularly produced LPA remains poorly understood. Here, we investigated the regulatory mechanism and functional role of a LPA-producing lysophospholipase D GDE4, also known as GDPD1, in prostate cancer cells. GDE4 expression is induced under ER stress conditions in a PERK-dependent manner and requires the transcription factor ATF3. Disruption of GDE4 expression resulted in altered intracellular levels of LPA and LPA precursor lysophosphatidylethanolamine, accompanied by reduced cell proliferation. RNA sequencing and subsequent validation identified a set of genes downregulated in GDE4-depleted cells. Pharmacological inhibition experiments indicated that peroxisome proliferator-activated receptor and {gamma} (PPAR and PPAR{gamma}) signaling pathways contribute to the regulation of these GDE4-dependent genes. Collectively, our findings suggest that GDE4-dependent lipid remodeling is associated with PPAR/{gamma}-mediated transcriptional regulation under ER stress conditions. These results provide a potential framework for understanding the link between intracellular lipid metabolism and stress-responsive gene regulation.
ER  -

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