Integrin α5β1 regulates PP2A complex assembly through PDE4D in atherosclerosis
Sanguk Yun, … , David C. Pallas, Martin A. Schwartz
Sanguk Yun, … , David C. Pallas, Martin A. Schwartz
Published November 1, 2019; First published August 13, 2019
Citation Information: J Clin Invest. 2019;129(11):4863-4874. https://doi.org/10.1172/JCI127692.
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Research Article Cell biology Vascular biology

Integrin α5β1 regulates PP2A complex assembly through PDE4D in atherosclerosis

Abstract

Fibronectin in the vascular wall promotes inflammatory activation of the endothelium during vascular remodeling and atherosclerosis. These effects are mediated in part by fibronectin binding to integrin α5, which recruits and activates phosphodiesterase 4D5 (PDE4D5) by inducing its dephosphorylation on an inhibitory site, S651. Active PDE then hydrolyzes antiinflammatory cAMP to facilitate inflammatory signaling. To test this model in vivo, we mutated the integrin binding site of PDE4D5 in mice. This mutation reduced endothelial inflammatory activation in atherosclerosis-prone regions of arteries and, in a hyperlipidemia model, reduced atherosclerotic plaque size while increasing markers of plaque stability. We then investigated the mechanism of PDE4D5 activation. Proteomics identified the PP2A regulatory subunit B55α as the factor recruiting PP2A to PDE4D5. The B55α-PP2A complex localized to adhesions and directly dephosphorylated PDE4D5. This interaction also, unexpectedly, stabilized the PP2A-B55α complex. The integrin-regulated, proatherosclerotic transcription factor Yap was also dephosphorylated and activated through this pathway. PDE4D5 therefore mediated matrix-specific regulation of endothelial cell phenotype via an unconventional adapter role, assembling and anchoring a multifunctional PP2A complex that has other targets. We believe these results may have widespread consequences for the control of cell function by integrins.

Authors

Sanguk Yun, Rui Hu, Melanie E. Schwaemmle, Alexander N. Scherer, Zhenwu Zhuang, Anthony J. Koleske, David C. Pallas, Martin A. Schwartz

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Figure 1

PDE4Dmut mice show reduced inflammation in a region of disturbed flow.

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PDE4Dmut mice show reduced inflammation in a region of disturbed flow. ...
(A) In the gene-editing strategy, 2 guide RNAs with Cas9 nickase were used with donor ssDNA to induce the KKKR-to-EEEE mutation. (B) Confirmation of the mutation. The female founder mouse (no. 1422) identified by PCR with mutant-specific primers in Supplemental Figure 1A was confirmed by sequencing of genomic DNA. (C) Longitudinal sections from aortae from 3-month-old WT and mutant mice were stained for the indicated inflammatory markers. Images show the inner curvature of the aortic arch. The intensity for each marker in the endothelial layer was quantified as described in Methods, and the intensity in the inner curvature was normalized to signal from the outer curvature. Values indicate the mean ± SEM. P values were determined by 2-tailed Student’s t test. Scale bar: 70 μm.