HSPB7 is indispensable for heart development by modulating actin filament assembly

Tongbin Wu, Yongxin Mu, Julius Bogomolovas, Xi Fang, Jennifer Veevers, Roberta B. Nowak, Christopher T. Pappas, Carol Gregorio, Sylvia M. Evans, Velia M. Fowler, Ju Chen

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Small heat shock protein HSPB7 is highly expressed in the heart. Several mutations within HSPB7 are associated with dilated cardiomyopathy and heart failure in human patients. However, the precise role of HSPB7 in the heart is still unclear. In this study, we generated global as well as cardiac-specific HSPB7 KO mouse models and found that loss of HSPB7 globally or specifically in cardiomyocytes resulted in embryonic lethality before embryonic day 12.5. Using biochemical and cell culture assays, we identified HSPB7 as an actin filament length regulator that repressed actin polymerization by binding to monomeric actin. Consistent with HSPB7’s inhibitory effects on actin polymerization, HSPB7 KO mice had longer actin/thin filaments and developed abnormal actin filament bundles within sarcomeres that interconnected Z lines and were cross-linked by α-actinin. In addition, loss of HSPB7 resulted in up-regulation of Lmod2 expression and mislocalization of Tmod1. Furthermore, crossing HSPB7 null mice into an Lmod2 null background rescued the elongated thin filament phenotype of HSPB7 KOs, but double KO mice still exhibited formation of abnormal actin bundles and early embryonic lethality. These in vivo findings indicated that abnormal actin bundles, not elongated thin filament length, were the cause of embryonic lethality in HSPB7 KOs. Our findings showed an unsuspected and critical role for a specific small heat shock protein in directly modulating actin thin filament length in cardiac muscle by binding monomeric actin and limiting its availability for polymerization.

Original languageEnglish (US)
Pages (from-to)11956-11961
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number45
DOIs
StatePublished - Nov 7 2017

Keywords

  • Actin polymerization
  • Heart development
  • HSPB7
  • Sarcomere
  • Thin filament assembly

ASJC Scopus subject areas

  • General

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    Wu, T., Mu, Y., Bogomolovas, J., Fang, X., Veevers, J., Nowak, R. B., Pappas, C. T., Gregorio, C., Evans, S. M., Fowler, V. M., & Chen, J. (2017). HSPB7 is indispensable for heart development by modulating actin filament assembly. Proceedings of the National Academy of Sciences of the United States of America, 114(45), 11956-11961. https://doi.org/10.1073/pnas.1713763114