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ResearchIn-Press PreviewCardiologyCell biology Open Access | 10.1172/JCI163730

Phosphorylation of CRYAB induces a condensatopathy to worsen post-myocardial infarction left ventricular remodeling

Moydul Islam,1 David R. Rawnsley,1 Xiucui Ma,1 Walter Navid,1 Chen Zhao,1 Xumin Guan,1 Layla Foroughi,2 John T. Murphy,1 Honora Navid,1 Carla J. Weinheimer,1 Attila Kovacs,1 Jessica Nigro,1 Aaradhya Diwan,1 Ryan P. Chang,1 Minu Kumari,1 Martin E. Young,3 Babak Razani,1 Kenneth B. Margulies,4 Mahmoud Abdellatif,5 Simon Sedej,5 Ali Javaheri,1 Douglas F. Covey,6 Kartik Mani,1 and Abhinav Diwan1

1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

2Division of Cardiology, Department of Medicine Medicine, Washington University School of Medicine, St. Louis, United States of America

3Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

4Heart Failure and Transplant Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

5Department of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

6Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States of America

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Published February 11, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI163730.
Copyright © 2025, Islam et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 11, 2025 - Version history
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Abstract

Protein aggregates are emerging therapeutic targets in rare monogenic causes of cardiomyopathy and amyloid heart disease, but their role in more prevalent heart failure syndromes remains mechanistically unexamined. We observed mis-localization of desmin and sarcomeric proteins to aggregates in human myocardium with ischemic cardiomyopathy and in mouse hearts with post-myocardial infarction ventricular remodeling, mimicking findings of autosomal-dominant cardiomyopathy induced by R120G mutation in the cognate chaperone protein, CRYAB. In both syndromes, we demonstrate increased partitioning of CRYAB phosphorylated on serine-59 to NP40-insoluble aggregate-rich biochemical fraction. While CRYAB undergoes phase separation to form condensates, the phospho-mimetic mutation of serine-59 to aspartate (S59D) in CRYAB mimics R120G-CRYAB mutants with reduced condensate fluidity, formation of protein aggregates and increased cell death. Conversely, changing serine to alanine (phosphorylation-deficient mutation) at position 59 (S59A) restored condensate fluidity, and reduced both R120G-CRYAB aggregates and cell death. In mice, S59D CRYAB knock-in was sufficient to induce desmin mis-localization and myocardial protein aggregates, while S59A CRYAB knock-in rescued left ventricular systolic dysfunction post-myocardial infarction and preserved desmin localization with reduced myocardial protein aggregates. 25-Hydroxycholesterol attenuated CRYAB serine-59 phosphorylation and rescued post-myocardial infarction adverse remodeling. Thus, targeting CRYAB phosphorylation-induced condensatopathy is an attractive strategy to counter ischemic cardiomyopathy.

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