State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin 300070, China.
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin 300070, China; Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
Cell Rep. 2020 Aug 4;32(5):107990. doi: 10.1016/j.celrep.2020.107990.
The Hippo/Yes-associated protein (YAP) pathway has pivotal roles in innate immune responses against pathogens in macrophages. However, the role of YAP in macrophages during atherosclerosis and its mechanism of YAP activation remain unknown. Here, we find that YAP overexpression in myeloid cells aggravates atherosclerotic lesion size and infiltration of macrophages, whereas YAP deficiency reduces atherosclerotic plaque. Tumor necrosis factor receptor-associated factor 6 (TRAF6), a downstream effector of interleukin-1β (IL-1β), triggers YAP ubiquitination at K252, which interrupts the interaction between YAP and angiomotin and results in enhanced YAP nuclear translocation. The recombinant IL-1 receptor antagonist anakinra reduces atherosclerotic lesion formation, which is abrogated by YAP overexpression. YAP level is increased in human and mouse atherosclerotic vessels, and plasma IL-1β level in patients with STEMI is correlated with YAP protein level in peripheral blood mononuclear cells. These findings elucidate a mechanism of YAP activation, which might be a therapeutic target for atherosclerosis.
Hippo/Yes 相关蛋白 (YAP) 通路在巨噬细胞固有免疫反应中对抗病原体起着关键作用。然而，YAP 在动脉粥样硬化过程中在巨噬细胞中的作用及其激活机制尚不清楚。在这里，我们发现髓系细胞中 YAP 的过表达会加重动脉粥样硬化病变的大小和巨噬细胞的浸润，而 YAP 的缺失则会减少动脉粥样硬化斑块。肿瘤坏死因子受体相关因子 6（TRAF6）是白细胞介素 1β（IL-1β）的下游效应物，它触发 YAP 在 K252 处的泛素化，从而中断 YAP 与血管生成素的相互作用，导致 YAP 核转位增强。重组白细胞介素 1 受体拮抗剂 anakinra 可减少动脉粥样硬化病变的形成，而过表达 YAP 则可消除这种作用。人动脉粥样硬化血管和小鼠动脉粥样硬化血管中 YAP 水平升高，STEMI 患者的血浆 IL-1β 水平与外周血单核细胞中的 YAP 蛋白水平相关。这些发现阐明了 YAP 激活的机制，这可能是动脉粥样硬化的治疗靶点。
