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ZFIN ID: ZDB-PUB-180115-2
Hspb7 is a Cardioprotective Chaperone Facilitating Sarcomeric Proteostasis
Mercer, E.J., Lin, Y.F., Cohen-Gould, L., Evans, T.
Date: 2018
Source: Developmental Biology 435(1): 41-55 (Journal)
Registered Authors: Evans, Todd
Keywords: FilaminC, cardiomyopathy, hESCs, heart development, zebrafish
MeSH Terms:
  • Animals
  • Autophagy/genetics
  • Cardiomyopathies/embryology*
  • Cardiomyopathies/genetics
  • Cardiomyopathies/pathology
  • Filamins/genetics
  • Filamins/metabolism
  • HSP27 Heat-Shock Proteins/genetics
  • HSP27 Heat-Shock Proteins/metabolism*
  • Humans
  • Myocytes, Cardiac/metabolism
  • Myocytes, Cardiac/pathology
  • Proteostasis*
  • Sarcomeres/genetics
  • Sarcomeres/metabolism*
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 29331499 Full text @ Dev. Biol.
Small heat shock proteins are chaperones with variable mechanisms of action. The function of cardiac family member Hspb7 is unknown, despite being identified through GWAS as a potential cardiomyopathy risk gene. We discovered that zebrafish hspb7 mutants display mild focal cardiac fibrosis and sarcomeric abnormalities. Significant mortality was observed in adult hspb7 mutants subjected to exercise stress, demonstrating a genetic and environmental interaction that determines disease outcome. We identified large sarcomeric proteins FilaminC and Titin as Hspb7 binding partners in cardiac cells. Damaged FilaminC undergoes autophagic processing to maintain sarcomeric homeostasis. Loss of Hspb7 in zebrafish or human cardiomyocytes stimulated autophagic pathways and expression of the sister gene encoding Hspb5. Inhibiting autophagy caused FilaminC aggregation in HSPB7 mutant human cardiomyocytes and developmental cardiomyopathy in hspb7 mutant zebrafish embryos. These studies highlight the importance of damage-processing networks in cardiomyocytes, and a previously unrecognized role in this context for Hspb7.