14-3-3 binding motif phosphorylation disrupts Hdac4-organized condensates to stimulate cardiac reprogramming

Liu Liu; Ienglam Lei; Shuo Tian; Wenbin Gao; Yijing Guo; Zhaokai Li; Ziad Sabry; Paul Tang; Y. Eugene Chen; Zhong Wang

Cell Reports (Apr 2024)

14-3-3 binding motif phosphorylation disrupts Hdac4-organized condensates to stimulate cardiac reprogramming

Liu Liu,
Ienglam Lei,
Shuo Tian,
Wenbin Gao,
Yijing Guo,
Zhaokai Li,
Ziad Sabry,
Paul Tang,
Y. Eugene Chen,
Zhong Wang

Affiliations

Liu Liu: Department of Cardiac Surgery, Frankel Cardiovascular Center, The University of Michigan, Ann Arbor, MI 48109, USA
Ienglam Lei: Department of Cardiac Surgery, Frankel Cardiovascular Center, The University of Michigan, Ann Arbor, MI 48109, USA
Shuo Tian: Department of Cardiac Surgery, Frankel Cardiovascular Center, The University of Michigan, Ann Arbor, MI 48109, USA
Wenbin Gao: Department of Cardiac Surgery, Frankel Cardiovascular Center, The University of Michigan, Ann Arbor, MI 48109, USA
Yijing Guo: Department of Cardiac Surgery, Frankel Cardiovascular Center, The University of Michigan, Ann Arbor, MI 48109, USA
Zhaokai Li: Department of Cardiac Surgery, Frankel Cardiovascular Center, The University of Michigan, Ann Arbor, MI 48109, USA
Ziad Sabry: Department of Cardiac Surgery, Frankel Cardiovascular Center, The University of Michigan, Ann Arbor, MI 48109, USA
Paul Tang: Department of Cardiac Surgery, Frankel Cardiovascular Center, The University of Michigan, Ann Arbor, MI 48109, USA
Y. Eugene Chen: Department of Cardiac Surgery, Frankel Cardiovascular Center, The University of Michigan, Ann Arbor, MI 48109, USA
Zhong Wang: Department of Cardiac Surgery, Frankel Cardiovascular Center, The University of Michigan, Ann Arbor, MI 48109, USA; Corresponding author

Journal volume & issue: Vol. 43, no. 4
p. 114054

Abstract

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Summary: Cell fate conversion is associated with extensive post-translational modifications (PTMs) and architectural changes of sub-organelles, yet how these events are interconnected remains unknown. We report here the identification of a phosphorylation code in 14-3-3 binding motifs (PC14-3-3) that greatly stimulates induced cardiomyocyte (iCM) formation from fibroblasts. PC14-3-3 is identified in pivotal functional proteins for iCM reprogramming, including transcription factors and chromatin modifiers. Akt1 kinase and protein phosphatase 2A are the key writer and key eraser of the PC14-3-3 code, respectively. PC14-3-3 activation induces iCM formation with the presence of only Tbx5. In contrast, PC14-3-3 inhibition by mutagenesis or inhibitor-mediated code removal abolishes reprogramming. We discover that key PC14-3-3-embedded factors, such as histone deacetylase 4 (Hdac4), Mef2c, and Foxo1, form Hdac4-organized inhibitory nuclear condensates. PC14-3-3 activation disrupts Hdac4 condensates to promote cardiac gene expression. Our study suggests that sub-organelle dynamics regulated by a PTM code could be a general mechanism for stimulating cell reprogramming.

CP: Molecular biology

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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