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

Liu, Mingming; Meng, Yan; Lv, Huizhen; Wang, Biqing; Lv, Xue; Zhang, Hang; Xiang, Song; Du, Jie; Liu, Tong; Tian, Yikui; Zhang, Xu; Zhou, Fangfang; Cheng, Tao; Zhu, Yi; Jiang, Hongfeng; Cao, Yihai; Ai, Ding

doi:10.1016/j.celrep.2020.107990

Cited by 75 publications

(63 citation statements)

References 50 publications

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“…Our data support this cardiac fibroblast YAP-mediated mechanism, which may modulate immune cell behavior in the heart. These findings add to a growing literature describing a complex and likely cell-type and context-dependent Hippo-YAP involvement in inflammatory regulation 38 , 40 – 47 .…”

Section: Discussionsupporting

confidence: 66%

“…Our current findings using ChIP, qPCR, and luciferase reporter assays indicate that YAP occupies the Ccl2 promoter and exerts positive regulation of Ccl2 transcription in cardiac fibroblasts. This is not without precedent, as prior work has demonstrated that YAP occupies the Ccl2 gene and increases Ccl2 expression in mouse liver 37 , mouse macrophages 38 , and a human hepatocyte cell line 39 . Induction of pro-inflammatory chemokines, including Ccl2, was also reported in a mouse model of fibroblast Lats1/2 deficiency 30 .…”

Section: Discussionmentioning

confidence: 99%

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AAV-mediated YAP expression in cardiac fibroblasts promotes inflammation and increases fibrosis

Francisco

Nakada

Jeong

et al. 2021

Sci Rep

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Fibrosis is a hallmark of heart disease independent of etiology and is thought to contribute to impaired cardiac dysfunction and development of heart failure. However, the underlying mechanisms that regulate the differentiation of fibroblasts to myofibroblasts and fibrotic responses remain incompletely defined. As a result, effective treatments to mitigate excessive fibrosis are lacking. We recently demonstrated that the Hippo pathway effector Yes-associated protein (YAP) is an important mediator of myofibroblast differentiation and fibrosis in the infarcted heart. Yet, whether YAP activation in cardiac fibroblasts is sufficient to drive fibrosis, and how fibroblast YAP affects myocardial inflammation, a significant component of adverse cardiac remodeling, are largely unknown. In this study, we leveraged adeno-associated virus (AAV) to target cardiac fibroblasts and demonstrate that chronic YAP expression upregulated indices of fibrosis and inflammation in the absence of additional stress. YAP occupied the Ccl2 gene and promoted Ccl2 expression, which was associated with increased macrophage infiltration, pro-inflammatory cytokine expression, collagen deposition, and cardiac dysfunction in mice with cardiac fibroblast-targeted YAP overexpression. These results are consistent with other recent reports and extend our understanding of YAP function in modulating fibrotic and inflammatory responses in the heart.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

AAV-mediated YAP expression in cardiac fibroblasts promotes inflammation and increases fibrosis

Francisco

Nakada

Jeong

et al. 2021

Sci Rep

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“…Protein ubiquitination plays a very important role in cellular processes such as subcellular localization, growth, apoptosis and metabolism. The ubiquitination modification omics based on mass spectrometry has been used for disease biomarkers and pathogenic mechanism analysis [77,78]. In this project, we studied the ubiquitin proteomics of OACC tumor and adjacent normal tissues, identified the different ubiquitin modification sites, analyzed the function of the identified ubiquitinated proteins, and obtained 8 protein clusters.…”

Section: Discussionmentioning

confidence: 99%

Quantitative ubiquitylomics reveals the ubiquitination regulation landscape in oral adenoid cystic carcinoma

et al. 2021

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Adenoid cystic carcinoma (ACC) is an extremely rare salivary gland tumor with a poor prognosis and needs attention on molecular mechanisms. Protein ubiquitination is an evolutionarily conserved post-translational modification (PTM) for substrates degradation and control diverse cellular functions. The board cellular function of ubiquitination network holds great promise to detect potential targets and identify respective receptors. Novel technologies are discovered for in-depth research and characterization the precise and dynamic regulation of ubiquitylomics in multiple cellular processes during cancer initiation, progression and treatment. In this study, 4D label free quantitative techniques of ubiquitination proteomics were used and we identified a total of 4152 ubiquitination sites in 1993 proteins. We also performed a systematic bioinformatics analysis for differential modified proteins and peptides containing quantitative information through the comparation between OACC tumor with adjacent normal tissues, as well as the identification of 8 protein clusters with motif analysis. Our findings offered an important reference of potential biomarkers and effective therapeutic targets for ACC.

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“…Another K63-linked ubiquitination site on YAP upregulates YAP levels in macrophages in atherosclerosis lesions [141]. The K252 residue located in the WW2 domain of YAP is ubiquitinated by tumor necrosis factor receptor-associated factor 6 (TRAF6), the downstream effector of interleukin-1b (IL-1b).…”

Section: K252/k63-linked Ubiquitinationmentioning

confidence: 99%

Role of the Hippo pathway and mechanisms for controlling cellular localization of YAP/TAZ

2021

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The Hippo pathway is a crucial signaling mechanism that inhibits the growth of cells and organs during development and in disease. When the Hippo pathway is activated, YAP/TAZ transcriptional coactivators are phosphorylated by upstream kinases, preventing nuclear localization of YAP/TAZ. However, when the Hippo pathway is inhibited, YAP/TAZ localize mainly in the nucleus and induce the expression of target genes related to cell proliferation. Abnormal proliferation of cells is one of the hallmarks of cancer initiation, and activation of Hippo pathway dampens such cell proliferation. Various types of diseases including cancer can occur due to the dysregulation of the Hippo pathway. Therefore, a better understanding of the Hippo pathway signaling mechanisms, and in particular how YAP/TAZ exist in the nucleus, may lead to the identification of new therapeutic targets for treating cancer and other diseases. In this review,

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

Cited by 75 publications

References 50 publications

AAV-mediated YAP expression in cardiac fibroblasts promotes inflammation and increases fibrosis

AAV-mediated YAP expression in cardiac fibroblasts promotes inflammation and increases fibrosis

Quantitative ubiquitylomics reveals the ubiquitination regulation landscape in oral adenoid cystic carcinoma

Role of the Hippo pathway and mechanisms for controlling cellular localization of YAP/TAZ

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