Thrombin-Par1 signaling axis disrupts COP9 signalosome subunit 3-mediated ABCA1 stabilization in inducing foam cell formation and atherogenesis
Thrombin-Par1 signaling axis disrupts COP9 signalosome subunit 3-mediated ABCA1 stabilization in inducing foam cell formation and atherogenesis
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DOI：
10.1038/s41418-020-00623-9
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发表时间：
2020-09-23
影响因子：
12.4
通讯作者：
Rao, Gadiparthi N.
中科院分区：
文献类型：
--
作者：
Boro, Monoranjan;Govatati, Suresh;Rao, Gadiparthi N.
ATP结合盒转运体A1（ABCA 1）和G1（ABCG 1）在促进胆固醇流出中起重要作用。尽管这些转运蛋白的调节异常被认为是动脉粥样硬化形成的机制之一，但导致其功能障碍的原因还没有得到很好的研究。以前，我们已经报道了凝血酶对ABCG 1水平没有任何影响，但会消耗影响胆固醇流出的ABCA 1水平。在这项研究中，我们探讨了凝血酶诱导的ABCA 1水平在巨噬细胞和平滑肌细胞中的耗竭的机制。在正常生理条件下，发现COP 9信号体亚基3（CSN 3）与ABCA 1复合存在，并且在促动脉粥样硬化刺激物如凝血酶的存在下，ABCA 1被磷酸化并从CSN 3解离，导致其降解。CSN 3的强制表达抑制凝血酶诱导的ABCA 1泛素化和降解，恢复胆固醇流出并抑制泡沫细胞形成。在西方饮食（WD）喂养的ApoE（-/-）小鼠中，CSN 3也与ABCA 1解离，否则在普通饮食（CD）喂养的ApoE（-/-）小鼠中保持为复合物。有趣的是，WD喂养的ApoE（-/-）小鼠中CSN 3水平的消耗显著降低了ABCA 1水平，抑制了胆固醇流出并增强了泡沫细胞形成，从而加剧了载脂动脉粥样硬化斑块的形成。机制研究已经揭示了Par 1-G alpha（12）-Pyk 2-Gab 1-PKC theta信号转导参与触发ABCA 1的磷酸化及其与CSN 3的解离，从而减少胆固醇流出并放大泡沫细胞形成。此外，尽管发现CSN 3和ABCA 1在人非病变冠状动脉中共定位，但它们的水平在晚期动脉粥样硬化病变中降低并且彼此分离。总之，这些观察结果首次揭示了CSN 3的抗动脉粥样硬化作用，因此，设计保护其与ABCA 1相互作用的治疗药物可能对动脉粥样硬化有益。
ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1) play a vital role in promoting cholesterol efflux. Although, the dysregulation of these transporters was attributed as one of the mechanisms of atherogenesis, what renders their dysfunction is not well explored. Previously, we have reported that thrombin without having any effect on ABCG1 levels depletes ABCA1 levels affecting cholesterol efflux. In this study, we explored the mechanisms underlying thrombin-induced depletion of ABCA1 levels both in macrophages and smooth muscle cells. Under normal physiological conditions, COP9 signalosome subunit 3 (CSN3) was found to exist in complex with ABCA1 and in the presence of proatherogenic stimulants such as thrombin, ABCA1 was phosphorylated and dissociated from CSN3, leading to its degradation. Forced expression of CSN3 inhibited thrombin-induced ABCA1 ubiquitination and degradation, restored cholesterol efflux and suppressed foam cell formation. In Western diet (WD)-fed ApoE(-/-)mice, CSN3 was also disassociated from ABCA1 otherwise remained as a complex in Chow diet (CD)-fed ApoE(-/-)mice. Interestingly, depletion of CSN3 levels in WD-fed ApoE(-/-)mice significantly lowered ABCA1 levels, inhibited cholesterol efflux and intensified foam cell formation exacerbating the lipid laden atherosclerotic plaque formation. Mechanistic studies have revealed the involvement of Par1-G alpha(12)-Pyk2-Gab1-PKC theta signaling in triggering phosphorylation of ABCA1 and its disassociation from CSN3 curtailing cholesterol efflux and amplifying foam cell formation. In addition, although both CSN3 and ABCA1 were found to be colocalized in human non-lesion coronary arteries, their levels were decreased as well as dissociated from each other in advanced atherosclerotic lesions. Together, these observations reveal for the first time an anti-atherogenic role of CSN3 and hence, designing therapeutic drugs protecting its interactions with ABCA1 could be beneficial against atherosclerosis.