2. Academic Validation
  3. Macrophage K63-Linked Ubiquitination of YAP Promotes Its Nuclear Localization and Exacerbates Atherosclerosis

Macrophage K63-Linked Ubiquitination of YAP Promotes Its Nuclear Localization and Exacerbates Atherosclerosis

  • Cell Rep. 2020 Aug 4;32(5):107990. doi: 10.1016/j.celrep.2020.107990.
Mingming Liu 1,  Meng Yan 1,  Huizhen Lv 2,  Biqing Wang 1,  Xue Lv 3,  Hang Zhang 1,  Song Xiang 1,  Jie Du 4,  Tong Liu 5,  Yikui Tian 6,  Xu Zhang 5,  Fangfang Zhou 7,  Tao Cheng 2,  Yi Zhu 1,  Hongfeng Jiang 8,  Yihai Cao 9,  Ding Ai 10
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
  • 4 Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
  • 5 Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, the Second Hospital of Tianjin Medical University, Tianjin 300211, China.
  • 6 Department of Cardiovascular Surgery, Tianjin Medical University General Hospital, Tianjin 300070, China.
  • 7 Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China.
  • 8 Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China. Electronic address: [email protected].
  • 9 Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 17177 Stockholm, Sweden. Electronic address: [email protected].
  • 10 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. Electronic address: [email protected].
PMID: 32755583 DOI: 10.1016/j.celrep.2020.107990
Abstract

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.

Keywords

IL-1β; YAP; atherosclerosis; inflammation; macrophages.

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