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E3 Ligase FBXW2 Is a New Therapeutic Target in Obesity and Atherosclerosis

Cheng Wang1,2, Wenjing Xu1, Yuelin Chao3

  • 1Clinic Center of Human Gene Research Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430022 China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|October 26, 2020
PubMed

Insights

The E3 ubiquitin ligase FBXW2 (F-box/WD Repeat-Containing Protein 2) drives inflammation in macrophages, worsening obesity and atherosclerosis. Inhibiting FBXW2 or its target KSRP offers potential treatments for these metabolic diseases.

Area of Science:

  • Biochemistry
  • Immunology
  • Metabolic Diseases

Background:

  • Chronic low-grade inflammation in macrophages is central to metabolic diseases like obesity and atherosclerosis.
  • The precise molecular mechanisms driving this inflammation require further elucidation.

Purpose of the Study:

  • To identify novel inflammatory mediators in macrophages involved in metabolic diseases.
  • To investigate the role of the E3 ubiquitin ligase FBXW2 (F-box/WD Repeat-Containing Protein 2) in macrophage-mediated inflammation.
  • To explore therapeutic strategies targeting FBXW2 and its downstream effectors.

Main Methods:

  • Utilized myeloid-specific FBXW2 gene-deficient murine models.
  • Investigated FBXW2's role in obesity, insulin resistance, and atherosclerosis.
  • Identified KH-type splicing regulatory protein (KSRP) as a ubiquitin substrate of SCFFBXW2.
  • Analyzed the function of the FBXW2 C-terminus (P3) as an inhibitor.

Main Results:

  • Myeloid-specific FBXW2 deficiency ameliorated obesity, insulin resistance, and atherosclerosis in mice.
  • FBXW2 knockout reduced pro-inflammatory responses and macrophage infiltration.
  • KSRP was identified as a key substrate; its inhibition impaired FBXW2-deficient macrophages' protective effects.
  • The FBXW2 P3 domain competitively inhibited KSRP degradation, reducing obesity and atherogenesis.

Conclusions:

  • SCFFBXW2 acts as a significant mediator in macrophage-driven metabolic diseases.
  • Targeting FBXW2, particularly its P3 domain, or KSRP ubiquitination presents a viable therapeutic avenue for obesity and atherosclerosis.
  • Developing FBXW2 (P3)-mimicking inhibitors could offer novel treatment strategies.
Keywords:
FBXW2KSRPatherosclerosisinflammationinsulin resistanceobesity

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