PUBLICATION
Hspb7 is a Cardioprotective Chaperone Facilitating Sarcomeric Proteostasis
- Authors
- Mercer, E.J., Lin, Y.F., Cohen-Gould, L., Evans, T.
- ID
- ZDB-PUB-180115-2
- 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.
Citation
Mercer, E.J., Lin, Y.F., Cohen-Gould, L., Evans, T. (2018) Hspb7 is a Cardioprotective Chaperone Facilitating Sarcomeric Proteostasis. Developmental Biology. 435(1):41-55.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping