HSPB7 is indispensable for heart development by modulating actin filament assembly

Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):11956-11961. doi: 10.1073/pnas.1713763114. Epub 2017 Oct 23.

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.

Keywords: HSPB7; actin polymerization; heart development; sarcomere; thin filament assembly.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / genetics
  • Actin Cytoskeleton / metabolism*
  • Animals
  • Cardiomyopathies / genetics*
  • Cytoskeletal Proteins / biosynthesis
  • Cytoskeletal Proteins / genetics
  • Female
  • HSP27 Heat-Shock Proteins / genetics*
  • Heart / embryology*
  • Heart Defects, Congenital / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Proteins / biosynthesis
  • Muscle Proteins / genetics
  • Myocardium / cytology
  • Myocytes, Cardiac / cytology
  • Organogenesis / genetics
  • Sarcomeres / metabolism
  • Tropomodulin / metabolism

Substances

  • Cytoskeletal Proteins
  • HSP27 Heat-Shock Proteins
  • HSPB7 protein, mouse
  • Muscle Proteins
  • Tmod1 protein, mouse
  • Tropomodulin
  • leiomodin protein, mouse