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

Mingming Liu1, Meng Yan1, Huizhen Lv2

  • 1State 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.

Cell Reports
|August 7, 2020
PubMed

Insights

The Yes-associated protein (YAP) pathway in macrophages exacerbates atherosclerosis by increasing lesion size. Interleukin-1β (IL-1β) activates YAP, presenting a potential therapeutic target for this cardiovascular disease.

Area of Science:

  • Immunology
  • Cardiovascular Biology
  • Molecular Biology

Background:

  • The Hippo/Yes-associated protein (YAP) pathway is crucial for macrophage innate immunity.
  • The specific role and activation mechanism of YAP in atherosclerosis remain unclear.

Purpose of the Study:

  • To investigate the role of YAP in macrophages during atherosclerosis.
  • To elucidate the mechanism of YAP activation in the context of atherosclerosis.

Main Methods:

  • Utilized mouse models of atherosclerosis with myeloid cell-specific YAP manipulation.
  • Investigated the interaction between YAP, angiomotin, and TRAF6.
  • Assessed the effect of anakinra, an IL-1 receptor antagonist, on atherosclerotic lesions.
  • Analyzed YAP and IL-1β levels in human and mouse atherosclerotic tissues and patient samples.

Main Results:

  • YAP overexpression in myeloid cells worsened atherosclerotic lesion size and macrophage infiltration.
  • YAP deficiency reduced atherosclerotic plaque development.
  • TRAF6-mediated ubiquitination of YAP at K252 disrupted YAP-angiomotin interaction, enhancing nuclear translocation.
  • Anakinra reduced lesion formation, an effect abolished by YAP overexpression.
  • Elevated YAP levels were observed in human and mouse atherosclerotic vessels.
  • Plasma IL-1β levels in STEMI patients correlated with peripheral blood mononuclear cell YAP levels.

Conclusions:

  • YAP activation, triggered by IL-1β via TRAF6, promotes atherosclerosis.
  • Targeting the IL-1β/TRAF6/YAP axis may offer a novel therapeutic strategy for atherosclerosis.
Keywords:
IL-1βYAPatherosclerosisinflammationmacrophages

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