TFEB SUMOylation In Macrophage Affects Foam Cell Formation And Atherosclerosis

Atherosclerosis(AS)has become the main cause of coronary heart disease,cerebral infarction and peripheral vascular disease.The disorder of lipid metabolism,especially hypercholesterolemia,is a major risk factor for atherosclerosis.In the course of atherosclerosis,macrophages can phagocytize and process low-density lipoprotein(LDL)which accumulated in peripheral tissues.Thus,macrophages play an important role in maintaining the homeostasis of LDL.As macrophages uptake too much lipid and the lipid looks like foam in cytoplasm,thus,we call this cell macrophage foam cells.Lysosomes are the major catabolism center of cells and lysosomes can hydrolyze cholesterol esters into free cholesterol,ultimately promoting the Reverse Cholesterol Transport(RCT)and alleviating intracellular lipid deposition.The disfunction of lysosome is associated with foam cell formation and AS pathogenesis.Transcription factor EB(TFEB)is a transcription factor,which plays an important role in regulating lysosome biogenesis and autophagy.TFEB is a SUMOylated protein.However,whether the SUMOylation of TFEB plays an important role in the formation of macrophage foam cells in atherosclerosis is not clear yet.In order to clarify whether the SUMOylation of TFEB plays an important role in the formation of macrophage foam cells in AS pathogenesis,we first test whetherTFEB SUMOylation would be altered in macrophages after Oxidized LDL(OxLDL)treatment.We found that the SUMOylation of TFEB decreased in macrophages after OxLDL treatment.We furher generated a TFEB SUMOylation deficiency K346R mouse model(Tfeb-KR),a Tfeb-KR crossed Ldlr-/-mouse model(Tfeb-KR;Ldlr-/-)to investigate the role of TFEB SUMOylation in AS pathogenesis in vivo.We found that the Tfeb-KR:Ldlr-/-atherosclerotic mice had fewer and thinner plaques than the corresponding wild type mice.We also found that macrophages in the Tfeb-KR:Ldlr-/-mice plaques had higher lysosomal activity.Furthermore,we found that under OxLDL stimulation,TFEB with the mutation of SUMOylation site has stronger transcriptional activity,which makes the Tfeb-KR macrophages have higher lysosomal activity.Ultimately,lipid deposition in the Tfeb-KR macrophages was less than that in the wild type macrophages.Finally,we found that the reason for the stronger transcriptional activity of TFEB with the mutation of SUMOylation site is that SUMOylation weakens the binding activity of TFEB to its target genes.These results suggest that the SUMOylation of TFEB is significantly reduced in atherosclerosis,which can enhance the transcriptional activity of TFEB,and ultimately inhibit the formation of macrophage foam cells by enhancing lysosome biogenesis and autophagy.Thereby reducing the accumulation of lipids in macrophages,and ultimately alleviating the occurrence and development of atherosclerosis.