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Hspb7 is a cardioprotective chaperone facilitating sarcomeric proteostasis.

TitleHspb7 is a cardioprotective chaperone facilitating sarcomeric proteostasis.
Publication TypeJournal Article
Year of Publication2018
AuthorsMercer, EJ, Lin, Y-F, Cohen-Gould, L, Evans, T
JournalDev Biol
Volume435
Issue1
Pagination41-55
Date Published2018 03 01
ISSN1095-564X
KeywordsAnimals, Autophagy, Cardiomyopathies, Filamins, HSP27 Heat-Shock Proteins, Humans, Myocytes, Cardiac, Proteostasis, Sarcomeres, Zebrafish, Zebrafish Proteins
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.

DOI10.1016/j.ydbio.2018.01.005
Alternate JournalDev. Biol.
PubMed ID29331499
PubMed Central IDPMC5818303
Grant ListR01 HL111400 / HL / NHLBI NIH HHS / United States
R35 HL135778 / HL / NHLBI NIH HHS / United States