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<p>The remodeling of the liver proteome, driven by dynamic ubiquitin-like post-translational modifications (PTMs) such as ubiquitination and NEDDylation, is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD). These PTMs enable rapid adaptation to environmental challenges by modulating protein stability and function. Using transgenic biotinylated ubiquitin and biotinylated NEDD8 mice, we profiled the hepatic ubiquitome and NEDDylome in a diet-induced MASLD model. Quantitative mass spectrometry identified over 1400 ubiquitinated proteins, with more than 600 proteins significantly altered in MASLD. Ubiquitinated proteins were enriched in processes related to endoplasmic reticulum and peroxisomal lipid metabolism, while NEDDylated targets primarily localized to mitochondrial pathways. Proteomic analysis revealed impaired proteasome function, endoplasmic reticulum stress, and mitochondrial dysfunction, suggesting that dysregulation of ubiquitin-like PTMs plays a critical role in MASLD. Our findings provide new insights into the distinct roles of ubiquitin and NEDD8 in MASLD. Further exploration of PTM crosstalk will enhance our understanding of MASLD pathophysiology.</p>

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Rearrangement of the liver ubiquitome and NEDDylome in metabolic dysfunction-associated steatotic liver disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月5日

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  • Teresa C. Delgado,
  • Benoît Lectez,
  • Marina Serrano-Maciá,
  • Fernando Lopitz-Otsoa,
  • Leire Uraga-Gracianteparaluceta,
  • Ibon Martínez-Arranz,
  • Jesús M. Arizmendi,
  • Kerman Aloria,
  • Mikel Azkargorta,
  • Félix Elortza,
  • James D. Sutherland,
  • Rosa Barrio,
  • Ugo Mayor,
  • María Luz Martínez-Chantar

摘要

The remodeling of the liver proteome, driven by dynamic ubiquitin-like post-translational modifications (PTMs) such as ubiquitination and NEDDylation, is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD). These PTMs enable rapid adaptation to environmental challenges by modulating protein stability and function. Using transgenic biotinylated ubiquitin and biotinylated NEDD8 mice, we profiled the hepatic ubiquitome and NEDDylome in a diet-induced MASLD model. Quantitative mass spectrometry identified over 1400 ubiquitinated proteins, with more than 600 proteins significantly altered in MASLD. Ubiquitinated proteins were enriched in processes related to endoplasmic reticulum and peroxisomal lipid metabolism, while NEDDylated targets primarily localized to mitochondrial pathways. Proteomic analysis revealed impaired proteasome function, endoplasmic reticulum stress, and mitochondrial dysfunction, suggesting that dysregulation of ubiquitin-like PTMs plays a critical role in MASLD. Our findings provide new insights into the distinct roles of ubiquitin and NEDD8 in MASLD. Further exploration of PTM crosstalk will enhance our understanding of MASLD pathophysiology.