Deubiquitination of CD36 by UCHL1 promotes foam cell formation

Xiaohong Xia,Ningning Liu,Shiming Liu,Jinchan He,Xiaolin Liu,Cuifu Yu,Tumei Hu,Qiong Xu,Hongbiao Huang,Xuke Chen,Mingke Liu

doi:10.1038/s41419-020-02888-x

Abstract

Atherosclerosis-associated cardiovascular diseases are main causes leading to high mortality worldwide. Macrophage-derived foam cell formation via uptaking modified lipoproteins is the initial and core step in the process of atherosclerosis. Meanwhile, scavenger receptor is indispensable for the formation of foam cells. UCHL1, a deubiquitinase, has been widely studied in multiple cancers. UCHL1 could be an oncogene or a tumor suppressor in dependent of tumor types. It remains unknown whether UCHL1 influences cellular oxLDL uptake. Herein we show that UCHL1 deletion significantly inhibits lipid accumulation and foam cell formation. Subsequently, we found that UCHL1 inhibitor or siRNA downregulates the expression of CD36 protein whereas SR-A, ABCA1, ABCG1, Lox-1, and SR-B1 have no significant change. Furthermore, the treatment of UCHL1 inhibition increases the abundance of K48-polyubiquitin on CD36 and the suppression of lipid uptake induced by UCHL1 deficiency is attenuated by blocking CD36 activation. Our study concluded that UCHL1 deletion decreases foam cell formation by promoting the degradation of CD36 protein, indicating UCHL1 may be a potential target for atherosclerosis treatment.

Highlights

Cardiovascular diseases have been the most common cause of mortality and morbidity all over the world[1,2]
We found that intracellular lipids in oxidized low-density lipoprotein (oxLDL) treatment group was more than that of in control using oil red O staining assays, suggesting that the macrophages were foamed and macrophage-derived foam cell formation (MFCF) model was successfully performed (Fig. 1a, b)
These results indicated that the foam cell formation was suppressed by Ubiquitin C-terminal hydrolase 1 (UCHL1) inhibitor or siRNA

Summary

Introduction

Cardiovascular diseases have been the most common cause of mortality and morbidity all over the world[1,2]. Atherosclerosis which is regarded as a chronic inflammatory disease is the fundamental pathological process underlying coronary artery disease (CAD) and stroke[3]. Atherosclerosis is caused mainly in large and medium arteries via recruiting immune cells to artery wall and disordering lipid metabolism[4,5]. The crucial early steps which recruited monocytes are differentiate into macrophages results from the retention of lipoproteins in subendothelial[6]. Macrophages undergo oxLDL receptor 1 (Lox-1), CD36, or scavenger receptor-A (SR-A)[7,8,9]. When macrophages are as cholesterol-laden foam cells, inflammatory responses are triggered to accelerate plaque formation[9]. Transformation of macrophage into foam cells is mediated by lipid uptake and cholesterol efflux. Cholesterol efflux is a result of disturbance of scavenger receptor class

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Results

Conclusion