Zdhhc1 deficiency mitigates foam cell formation and atherosclerosis by inhibiting PI3K-Akt-mTOR signaling pathway through facilitating the nuclear translocation of p110α

被引:0
|
作者
Zhou, Binhui [1 ,2 ,3 ]
Liu, Yang [1 ]
Ma, Haoyuan [1 ]
Zhang, Bowen [1 ]
Lu, Beijia [3 ]
Li, Sainan [3 ]
Liu, Tingting [1 ]
Qi, Yingcheng [1 ]
Wang, Ying [2 ,3 ]
Zhang, Mengjie [1 ]
Qiu, Juanjuan [1 ]
Fu, Rui [1 ]
Li, Wushan [1 ,3 ]
Lu, Liaoxun [1 ,3 ]
Tian, Shuanghua [1 ]
Liu, Qiaoli [1 ]
Gu, Yanrong [1 ]
Huang, Rong [1 ]
Lawrence, Toby [6 ,7 ]
Kong, Eryan [2 ,3 ]
Zhang, Lichen [1 ]
Li, Tianhan [1 ,4 ]
Liang, Yinming [1 ,3 ,5 ]
机构
[1] Xinxiang Med Univ, Sch Med Technol, Lab Genet Regulators Immune Syst, Xinxiang 453003, Peoples R China
[2] Xinxiang Med Univ, Affiliated Hosp 2, Xinxiang 453003, Peoples R China
[3] Xinxiang Med Univ, Inst Psychiat & Neurosci, Lab Mouse Genet, Xinxiang 453003, Peoples R China
[4] Xinxiang Med Univ, Basic Med Coll, Xinxiang 453003, Peoples R China
[5] Hunan Acad Chinese Med, Ctr Dis Model & Immunol, Changsha 410013, Peoples R China
[6] Kings Coll London, Ctr Inflammat Biol & Canc Immunol, London SE1 1UL, England
[7] Aix Marseille Univ, CNRS, INSERM, Ctr Immunol Marseille Luminy, F-13009 Marseille, France
来源
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | 2025年 / 1871卷 / 02期
基金
中国国家自然科学基金;
关键词
Zdhhc1; Palmitoylation; Foam cell formation; Atherosclerosis; PI3K-Akt-mTOR signaling pathway; PROTEIN PALMITOYLATION; MACROPHAGES; DISEASE; BIOLOGY;
D O I
10.1016/j.bbadis.2024.167577
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Monocyte-to-macrophage differentiation and subsequent foam cell formation are key processes that contribute to plaque build-up during the progression of atherosclerotic lesions. Palmitoylation enzymes are known to play pivotal roles in the development and progression of inflammatory diseases. However, their specific impact on atherosclerosis development remains unclear. In this study, we discovered that the knockout of zDHHC1 in THP1 cells, as well as Zdhhc1 in mice, markedly reduces the uptake of oxidized low-density lipoprotein (ox-LDL) by macrophages, thereby inhibiting foam cell formation. Moreover, the absence of Zdhhc1 in ApoE- /- mice significantly suppresses atherosclerotic plaque formation. Mass spectrometry coupled with bioinformatic analysis revealed an enrichment of the PI3K-Akt-mTOR signaling pathway. Consistent with this, we observed that knockout of zDHHC1 significantly decreases the palmitoylation levels of p110 alpha, a crucial subunit of PI3K. Notably, the deletion of Zdhhc1 facilitates the nuclear translocation of p110 alpha in macrophages, leading to a significant reduction in the downstream phosphorylation of Akt at Ser473 and mTOR at Ser2448. This cascade results in a decreased number of macrophages within plaques and ultimately mitigates the severity of atherosclerosis. These findings unveil a novel role for zDHHC1 in regulating foam cell formation and the progression of atherosclerosis, suggesting it as a promising target for clinical intervention in atherosclerosis therapy.
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页数:13
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