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Background <p>Lipid droplets (LDs) are dynamic cytoplasmic lipid-storing organelles that play a pivotal role in maintaining cellular energy balance, lipid homeostasis, and metabolic signaling. Dysregulation of lipid metabolism, particularly excessive lipogenesis, contributes to the abnormal accumulation of LDs in the nervous system, which is associated with several neurodegenerative diseases. Circular RNAs (circRNAs) are a new class of non-coding and regulatory RNAs that are widely expressed in eukaryotes. However, only a subset has been functionally characterized. Here, we identified and functionally characterized a new circular RNA <i>circbabo(5,6,7,8S)</i> that regulates lipogenesis and neuronal integrity in <i>Drosophila melanogaster.</i></p> Results <p><i>circbabo(5,6,7,8S)</i> is derived from the <i>babo</i> locus which encodes the type I receptor for transforming growth factor β (TGF-β). Depletion of <i>circbabo(5,6,7,8S)</i> in flies causes elevated lipid droplet accumulation, progressive photoreceptor cell loss and shortened lifespan, phenotypes that are rescued by restoring <i>circbabo(5,6,7,8S)</i> expression. In addition, RNA-seq and epistasis analyses reveal that these abnormalities are caused by aberrant activation of the SREBP signaling pathway. Furthermore, <i>circbabo(5,6,7,8S)</i>-depleted tissues display enhanced activation of the TGF-β signaling pathway and compromised mitochondrial function, resulting in upregulation of reactive oxygen species (ROS). Moreover, we provide evidence that <i>circbabo(5,6,7,8S)</i> encodes the protein circbabo(5,6,7,8S)-p, which inhibits TGF-β signaling by interfering with the assembly of babo/put receptor heterodimer complex. Lastly, we show that dysregulation of the ROS/JNK/SREBP signaling cascade is responsible for the LD accumulation, neurodegeneration, and shortened lifespan phenotypes elicited by <i>circbabo(5,6,7,8S)</i> depletion.</p> Conclusions <p>Our study demonstrates the physiological role of the protein-coding circRNA <i>circbabo(5,6,7,8S)</i> in regulating lipid metabolism and neuronal integrity.</p>

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The circular RNA circbabo(5,6,7,8S) regulates lipid metabolism and neuronal integrity via TGF-β/ROS/JNK/SREBP signaling axis in Drosophila

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月5日

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  • Jie Sheng,
  • Xuemei Zhang,
  • Weihong Liang,
  • Junfang Lyu,
  • Bei Zhang,
  • Jie Min,
  • Austin Xu,
  • Xingyu Xu,
  • Jennifer W. Li,
  • Jian-Liang Li,
  • Rui Zhou,
  • Wei Liu

摘要

Background

Lipid droplets (LDs) are dynamic cytoplasmic lipid-storing organelles that play a pivotal role in maintaining cellular energy balance, lipid homeostasis, and metabolic signaling. Dysregulation of lipid metabolism, particularly excessive lipogenesis, contributes to the abnormal accumulation of LDs in the nervous system, which is associated with several neurodegenerative diseases. Circular RNAs (circRNAs) are a new class of non-coding and regulatory RNAs that are widely expressed in eukaryotes. However, only a subset has been functionally characterized. Here, we identified and functionally characterized a new circular RNA circbabo(5,6,7,8S) that regulates lipogenesis and neuronal integrity in Drosophila melanogaster.

Results

circbabo(5,6,7,8S) is derived from the babo locus which encodes the type I receptor for transforming growth factor β (TGF-β). Depletion of circbabo(5,6,7,8S) in flies causes elevated lipid droplet accumulation, progressive photoreceptor cell loss and shortened lifespan, phenotypes that are rescued by restoring circbabo(5,6,7,8S) expression. In addition, RNA-seq and epistasis analyses reveal that these abnormalities are caused by aberrant activation of the SREBP signaling pathway. Furthermore, circbabo(5,6,7,8S)-depleted tissues display enhanced activation of the TGF-β signaling pathway and compromised mitochondrial function, resulting in upregulation of reactive oxygen species (ROS). Moreover, we provide evidence that circbabo(5,6,7,8S) encodes the protein circbabo(5,6,7,8S)-p, which inhibits TGF-β signaling by interfering with the assembly of babo/put receptor heterodimer complex. Lastly, we show that dysregulation of the ROS/JNK/SREBP signaling cascade is responsible for the LD accumulation, neurodegeneration, and shortened lifespan phenotypes elicited by circbabo(5,6,7,8S) depletion.

Conclusions

Our study demonstrates the physiological role of the protein-coding circRNA circbabo(5,6,7,8S) in regulating lipid metabolism and neuronal integrity.