2. Academic Validation
  3. LIMA1 links the E3 ubiquitin ligase RNF40 to lipid metabolism

LIMA1 links the E3 ubiquitin ligase RNF40 to lipid metabolism

  • Cell Death Discov. 2024 Jun 22;10(1):298. doi: 10.1038/s41420-024-02072-6.
Zhan Liu # 1 2,  Kexin Fan # 3,  Aikedaimu Abudukeremu 1,  Min Gao 3,  Xinyue Tan 3,  Xiaojuan Mao 3,  Xinyu Li 1,  Wenting Ma 1,  Xusheng Ma 2,  Caolong Li 2,  Yinglai Yang 2,  Kangsheng Tu 4,  Jing Chen 5,  Yilei Zhang 6,  Yaqun Guan 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China.
  • 2 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xinjiang Second Medical College, Karamay, Xinjiang, China.
  • 3 The Institute of Molecular and Translational Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 4 Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 5 Department of Obstetrics, Xi 'an New Chang 'an Maternity Hospital, Xi'an, Shaanxi, China.
  • 6 The Institute of Molecular and Translational Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China. zhangyilei@xjtu.edu.cn.
  • 7 State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China. yaqunguan557@xjmu.edu.cn.
  • # Contributed equally.
PMID: 38909032 DOI: 10.1038/s41420-024-02072-6
Abstract

LIMA1 is a LIM domain and Actin binding 1 protein that acts as a skeleton protein to promote Cholesterol absorption, which makes it an ideal target for interfering with lipid metabolism. However, the detailed regulation of LIMA1 remains unclear. Here, we identified that ring finger protein 40 (RNF40), an E3 ubiquitin Ligase previously known as an epigenetic modifier to increase H2B ubiquitination, mediated the ubiquitination of LIMA1 and thereby promoted its degradation in a proteasome-dependent manner. Fraction studies revealed that the 1-166aa fragment of LIMA1 was indispensable for the interaction with RNF40, and at least two domains of RNF40 might mediate the association of RNF40 with LIMA1. Notably, treatment with simvastatin dramatically decreased the levels of CHO and TG in control cells rather than cells with overexpressed LIMA1. Moreover, RNF40 significantly decreased lipid content, which could be reversed by LIMA1 overexpression. These findings suggest that E3 ubiquitin Ligase RNF40 could directly target LIMA1 and promote its protein degradation in cytoplasm, leading to the suppression of lipid accumulation mediated by LIMA1. Collectively, this study unveils that RNF40 is a novel E3 ubiquitin Ligase of LIMA1, which underpins its high therapeutic value to combat dysregulation of lipid metabolism.

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