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

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 mislocalization 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 the 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 phosphomimetic 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 knockin was sufficient to induce desmin mislocalization and myocardial protein aggregates, while S59A CRYAB knockin rescued left ventricular systolic dysfunction after 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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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-02-11
DOI
https://doi.org/10.1172/jci163730
Citations
3
Primary Topic
Cardiovascular Function and Risk Factors
Type
article
Field-Weighted Citation Impact
4.16

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article

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

Martin Elliot Young, Kenneth B. Margulies, David R. Rawnsley, Ali Javaheri et al.
3 citations
Journal of Clinical Investigation
Cardiovascular Function and Risk Factors
4.16
article

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

Martin Elliot Young, Kenneth B. Margulies, David R. Rawnsley, Ali Javaheri, Minu Kumari, Kartik Mani, John T. Murphy, Walter Navid, Jessica Nigro, Aaradhya Diwan, Abhinav Diwan, Attila D Kovács, Layla Foroughi, Carla J. Weinheimer, Ryan Chang, Babak Razani, Simon Sedej, Douglas F. Covey, Mahmoud Abdellatif, Chen Zhao, Moydul Islam, Xumin Guan, Xiucui Ma, Honora Navid
article en
3 citations

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 mislocalization 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 the 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 phosphomimetic 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 knockin was sufficient to induce desmin mislocalization and myocardial protein aggregates, while S59A CRYAB knockin rescued left ventricular systolic dysfunction after 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.

Journal of Clinical InvestigationVol. 135(7)
University of Pittsburgh (US), Medical University of Graz (AT), Washington University in St. Louis (US), HCA Midwest Division (US), University of Alabama at Birmingham (US), University of Maribor (SI), BioTechMed-Graz (AT), Missouri Institute of Mental Health (US), John Cochran VA Medical Center (US), University of Pennsylvania (US)
U.S. Department of Veterans Affairs, American Heart Association, Children's Discovery Institute, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Openalex Percentile: Top 7%
Cardiovascular Function and Risk Factors
4.16
DOIOpen Access PDFOpenAlex
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