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Deubiquitination of CD36 by UCHL1 promotes foam cell formation

Xiaohong Xia1,2, Qiong Xu1, Mingke Liu1

  • 1Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, 510260, Guangzhou, China.

Cell Death & Disease
|August 18, 2020
PubMed

Insights

UCHL1 deletion inhibits foam cell formation in atherosclerosis by promoting CD36 protein degradation. This finding suggests UCHL1 as a potential therapeutic target for treating atherosclerosis and related cardiovascular diseases.

Area of Science:

  • Biochemistry
  • Cardiovascular Biology
  • Molecular Medicine

Background:

  • Atherosclerosis, a leading cause of global mortality, involves macrophage foam cell formation.
  • Scavenger receptors are crucial for foam cell development, driven by modified lipoprotein uptake.
  • Ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) is implicated in various cancers, but its role in atherosclerosis is unclear.

Purpose of the Study:

  • To investigate the role of UCHL1 in macrophage foam cell formation and lipid accumulation.
  • To determine the molecular mechanisms by which UCHL1 influences cellular uptake of modified lipoproteins.

Main Methods:

  • Utilized UCHL1 deletion models and pharmacological inhibitors/siRNA to modulate UCHL1 activity.
  • Assessed lipid accumulation and foam cell formation in macrophages.
  • Quantified the expression of scavenger receptors (CD36, SR-A, ABCA1, ABCG1, Lox-1, SR-B1) and CD36 ubiquitination.
  • Investigated the effect of CD36 blockade on lipid uptake.

Main Results:

  • UCHL1 deletion significantly inhibited lipid accumulation and foam cell formation.
  • UCHL1 inhibition downregulated CD36 expression, without affecting other scavenger receptors.
  • UCHL1 inhibition increased K48-polyubiquitination of CD36, suggesting enhanced degradation.
  • Blocking CD36 activation attenuated the suppression of lipid uptake caused by UCHL1 deficiency.

Conclusions:

  • UCHL1 deletion reduces foam cell formation by enhancing CD36 protein degradation.
  • UCHL1 plays a critical role in regulating CD36-mediated lipid uptake.
  • UCHL1 inhibition presents a potential therapeutic strategy for atherosclerosis treatment.

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