Dataset Information

P300/CBP Associated Factor (PCAF) Deficiency Enhances Diet-Induced Atherosclerosis in ApoE3^*Leiden Mice via Systemic Inhibition of Regulatory T Cells.

ABSTRACT: Background: Inflammatory stimuli induced by NF-kB drive atherosclerotic lesion formation. The epigenetic P300/CBP associated factor (PCAF) post-transcriptionally acetylates FoxP3, which is required for regulatory T-cell (Treg) differentiation and immune modulation. We hypothesize that PCAF deficiency affects atherosclerosis via regulation of regulatory Tregs. Method: ApoE3^*Leiden (n = 13) and ApoE3^*LeidenxPCAF^-/- (n = 13) were fed a high-fat diet (HFD) containing 1.25% cholesterol. Systemic FoxP3⁺ T cells were measured every 4 weeks by flow cytometry (n = 6). After 5-months of HFD, mice were euthanized, and hearts and blood were collected. IL-6 and TNFα concentrations were measured in plasma to identify systemic inflammatory responses. Compositional and morphometrical analyses were performed on the atherosclerotic lesions in the aortic sinuses. Results: After 5 months of HFD, plasma cholesterol concentrations were not different for ApoE3^*LeidenxPCAF^-/- compared to ApoE3^*Leiden mice. Expression of FoxP3 by systemic CD4⁺ T cells decreased 1.8 fold in ApoE3^*LeidenxPCAF^-/- after 5 months HFD and remained significantly reduced after 5 months of HFD. Systemic TNFα and IL-6 concentrations were comparable, whereas the atherosclerotic lesion size in ApoE3^*LeidenxPCAF^-/- mice was increased by 28% compared to ApoE3^*Leiden mice. In atherosclerotic lesions, no differences were observed in macrophage differentiation or VSMC content, although a small increase in collagen was identified. Conclusion: Our data show that PCAF deficiency resulted in a decrease in circulatory FoxP3⁺ regulatory T cells and ameliorated atherosclerotic lesions with no differences in systemic inflammation or macrophage differentiation in the atherosclerotic lesions. This suggests that PCAF regulates atherosclerosis via modulation of FoxP3⁺ regulatory T cell differentiation.

SUBMITTER: de Jong A

PROVIDER: S-EPMC7874080 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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P300/CBP Associated Factor (PCAF) Deficiency Enhances Diet-Induced Atherosclerosis in ApoE3*Leiden Mice via Systemic Inhibition of Regulatory T Cells.

de Jong Alwin A de Jong Rob C M RCM Peters Erna A EA Arens Ramon R Jukema J Wouter JW de Vries Margreet R MR Quax Paul H A PHA

Frontiers in cardiovascular medicine 20210115

Background: Inflammatory stimuli induced by NF-kB drive atherosclerotic lesion formation. The epigenetic P300/CBP associated factor (PCAF) post-transcriptionally acetylates FoxP3, which is required for regulatory T-cell (Treg) differentiation and immune modulation. We hypothesize that PCAF deficiency affects atherosclerosis via regulation of regulatory Tregs. Method: ApoE3*Leiden (n = 13) and ApoE3*LeidenxPCAF-/- (n = 13) were fed a hi ...[more]

PMID: 33585580

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Project description:BackgroundFascin is crucial for cancer cell filopodium formation and tumor metastasis, and is functionally regulated by post-translational modifications. However, whether and how Fascin is regulated by acetylation remains unclear. This study explored the regulation of Fascin acetylation and its corresponding roles in filopodium formation and tumor metastasis.MethodsImmunoprecipitation and glutathione-S-transferase pull-down assays were performed to examine the interaction between Fascin and acetyltransferase P300/CBP-associated factor (PCAF), and immunofluorescence was used to investigate their colocalization. An in vitro acetylation assay was performed to identify Fascin acetylation sites by using mass spectrometry. A specific antibody against acetylated Fascin was generated and used to detect the PCAF-mediated Fascin acetylation in esophageal squamous cell carcinoma (ESCC) cells using Western blotting by overexpressing and knocking down PCAF expression. An in vitro cell migration assay was performed, and a xenograft model was established to study in vivo tumor metastasis. Live-cell imaging and fluorescence recovery after photobleaching were used to evaluate the function and dynamics of acetylated Fascin in filopodium formation. The clinical significance of acetylated Fascin and PCAF in ESCC was evaluated using immunohistochemistry.ResultsFascin directly interacted and colocalized with PCAF in the cytoplasm and was acetylated at lysine 471 (K471) by PCAF. Using the specific anti-AcK471-Fascin antibody, Fascin was found to be acetylated in ESCC cells, and the acetylation level was consequently increased after PCAF overexpression and decreased after PCAF knockdown. Functionally, Fascin-K471 acetylation markedly suppressed in vitro ESCC cell migration and in vivo tumor metastasis, whereas Fascin-K471 deacetylation exhibited a potent oncogenic function. Moreover, Fascin-K471 acetylation reduced filopodial length and density, and lifespan of ESCC cells, while its deacetylation produced the opposite effect. In the filipodium shaft, K471-acetylated Fascin displayed rapid dynamic exchange, suggesting that it remained in its monomeric form owing to its weakened actin-bundling activity. Clinically, high levels of AcK471-Fascin in ESCC tissues were strongly associated with prolonged overall survival and disease-free survival of ESCC patients.ConclusionsFascin interacts directly with PCAF and is acetylated at lysine 471 in ESCC cells. Fascin-K471 acetylation suppressed ESCC cell migration and tumor metastasis by reducing filopodium formation through the impairment of its actin-bundling activity.

Dataset Information

P300/CBP Associated Factor (PCAF) Deficiency Enhances Diet-Induced Atherosclerosis in ApoE3^*Leiden Mice via Systemic Inhibition of Regulatory T Cells.

Publications

P300/CBP Associated Factor (PCAF) Deficiency Enhances Diet-Induced Atherosclerosis in ApoE3<sup>*</sup>Leiden Mice via Systemic Inhibition of Regulatory T Cells.

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