TFEB SUMOylation in macrophages accelerates atherosclerosis by promoting the formation of foam cells through inhibiting lysosomal activity

Abstract Atherosclerosis (AS) is a serious cardiovascular disease. One of its hallmarks is hyperlipidemia. Inhibiting the formation of macrophage foam cells is critical for alleviating AS. Transcription factor EB (TFEB) can limit the formation of macrophage foam cells by up-regulating lysosomal activity. We examined whether TFEB SUMOylation is involved in this progress during AS. In this study, we investigated the role of TFEB SUMOylation in macrophages in AS using TFEB SUMOylation deficiency Ldlr −/− (TFEB-KR: Ldlr −/− ) transgenic mice and TFEB-KR bone marrow–derived macrophages. We observed that TFEB-KR: Ldlr −/− atherosclerotic mice had thinner plaques and macrophages with higher lysosomal activity when compared to WT: Ldlr −/− mice. TFEB SUMOylation in macrophages decreased after oxidized low-density lipoprotein (OxLDL) treatment in vitro . Compared with wild type macrophages, TFEB-KR macrophages exhibited less lipid deposition after OxLDL treatment. Our study demonstrated that in AS, deSUMOylation of TFEB could inhibit the formation of macrophage foam cells through enhancing lysosomal biogenesis and autophagy, further reducing the accumulation of lipids in macrophages, and ultimately alleviating the development of AS. Thus, TFEB SUMOylation can be a switch to modulate macrophage foam cells formation and used as a potential target for AS therapy.