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SHR Neuro Cancer Cardio Lipid Metab Microb

Islam, M; Rawnsley, DR; Ma, X; Navid, W; Zhao, C; Guan, X; Foroughi, L; Murphy, JT; Navid, H; Weinheimer, CJ; Kovacs, A; Nigro, J; Diwan, A; Chang, RP; Kumari, M; Young, ME; Razani, B; Margulies, KB; Abdellatif, M; Sedej, S; Javaheri, A; Covey, DF; Mani, K; Diwan, A.
Phosphorylation of CRYAB induces a condensatopathy to worsen post-myocardial infarction left ventricular remodeling.
J Clin Invest. 2025; 135(7): Doi: 10.1172/JCI163730 [OPEN ACCESS]
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Co-authors Med Uni Graz

Abdellatif Mahmoud

Sedej Simon

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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 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.

Find related publications in this database (using NLM MeSH Indexing)

Animals - administration & dosage

Myocardial Infarction - metabolism, pathology, genetics

Mice - administration & dosage

Humans - administration & dosage

Phosphorylation - administration & dosage

alpha-Crystallin B Chain - metabolism, genetics

Ventricular Remodeling - administration & dosage

Male - administration & dosage

Mutation, Missense - administration & dosage

Amino Acid Substitution - administration & dosage

Desmin - metabolism, genetics

Cardiomyopathies - metabolism, genetics, pathology

Mice, Transgenic - administration & dosage

Female - administration & dosage

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