Integrated proteomics unveils nuclear PDE3A2 as a regulator of cardiac myocyte hypertrophy

Subramaniam, G. et al. (2023) Integrated proteomics unveils nuclear PDE3A2 as a regulator of cardiac myocyte hypertrophy. Circulation Research, 132(7), pp. 828-848. (doi: 10.1161/CIRCRESAHA.122.321448) (PMID:36883446)

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Background: Signaling by cAMP is organized in multiple distinct subcellular nanodomains regulated by cAMP-hydrolyzing PDEs (phosphodiesterases). Cardiac β-adrenergic signaling has served as the prototypical system to elucidate cAMP compartmentalization. Although studies in cardiac myocytes have provided an understanding of the location and properties of a handful of cAMP subcellular compartments, an overall view of the cellular landscape of cAMP nanodomains is missing. Methods: Here, we combined an integrated phosphoproteomics approach that takes advantage of the unique role that individual PDEs play in the control of local cAMP, with network analysis to identify previously unrecognized cAMP nanodomains associated with β-adrenergic stimulation. We then validated the composition and function of one of these nanodomains using biochemical, pharmacological, and genetic approaches and cardiac myocytes from both rodents and humans. Results: We demonstrate the validity of the integrated phosphoproteomic strategy to pinpoint the location and provide critical cues to determine the function of previously unknown cAMP nanodomains. We characterize in detail one such compartment and demonstrate that the PDE3A2 isoform operates in a nuclear nanodomain that involves SMAD4 (SMAD family member 4) and HDAC-1. Inhibition of PDE3 results in increased HDAC-1 phosphorylation, leading to inhibition of its deacetylase activity, derepression of gene transcription, and cardiac myocyte hypertrophic growth. Conclusions: We developed a strategy for detailed mapping of subcellular PDE-specific cAMP nanodomains. Our findings reveal a mechanism that explains the negative long-term clinical outcome observed in patients with heart failure treated with PDE3 inhibitors.

Item Type:Articles
Additional Information:This study was supported by grants from the British Heart Foundation (BHF; PG/15/5/31110 and RG/17/6/32944) and the BHF Centre of Research Excellence, Oxford (RE/13/1/30181, RE/18/3/34214, and RE/18/3/34214) and the Oxford NIHR Biomedical Research Centre to M. Zaccolo; the Horizon 2020 project Epic-XS (823839) to A.J.R. Heck; the Deutsche Forschungsgemeinschaft (program project grant, 394046635–SFB 1365) and the German Israeli Foundation (I-1452-203/13-2018) to E. Klussmann; the Netherlands Organisation for Health Research and Development ZonMW (MKMD project No. 114022504) and the European Research Council (ERC-CoG 101001746 MiniHEART) to M. Bellin; and the Stand Up to Cancer campaign for Cancer Research UK grant A29800 to S. Zanivan.
Glasgow Author(s) Enlighten ID:Zanivan, Professor Sara
Authors: Subramaniam, G., Schleicher, K., Kovanich, D., Zerio, A., Folkmanaite, M., Chao, Y.-C., Surdo, N. C., Koschinski, A., Hu, J., Scholten, A., Heck, A. J.R., Ercu, M., Sholokh, A., Chan Park, K., Klussmann, E., Meraviglia, V., Bellin, M., Zanivan, S., Hester, S., Mohammed, S., and Zaccolo, M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Circulation Research
Publisher:American Heart Association
ISSN (Online):1524-4571
Published Online:08 March 2023
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in Circulation Research 132(7): 828-848
Publisher Policy:Reproduced under a Creative Commons License

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