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

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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.

Authors

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