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HSPB7 is indispensable for heart development by modulating actin filament assembly
Tongbin Wu1, Yongxin Mu1, Julius Bogomolovas1,2
1Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093.
Insights
Small heat shock protein HSPB7 regulates actin filament length in the heart. Loss of HSPB7 causes embryonic lethality due to abnormal actin bundles, revealing its critical role in cardiac development.
Area of Science:
- Cardiovascular Biology
- Molecular Cell Biology
- Protein Biochemistry
Background:
- Small heat shock protein HSPB7 is abundant in the heart.
- Mutations in HSPB7 are linked to human heart conditions like dilated cardiomyopathy and heart failure.
- The exact function of HSPB7 in cardiac tissue remains largely unknown.
Purpose of the Study:
- To elucidate the specific role of HSPB7 in cardiac muscle.
- To investigate the consequences of HSPB7 deficiency on cardiac structure and function.
- To identify the molecular mechanisms underlying HSPB7's function in the heart.
Main Methods:
- Generation of global and cardiac-specific HSPB7 knockout (KO) mouse models.
- Biochemical assays and cell culture to study HSPB7's interaction with actin.
- Histological and biochemical analysis of cardiac tissue from KO mice.
- Genetic interaction studies involving Lmod2 and Tmod1.
Main Results:
- HSPB7 deficiency leads to embryonic lethality before day 12.5.
- HSPB7 directly binds monomeric actin, inhibiting actin polymerization and regulating thin filament length.
- HSPB7 KO mice exhibit elongated thin filaments and abnormal, α-actinin-crosslinked actin bundles in sarcomeres.
- Loss of HSPB7 upregulates Lmod2 and mislocalizes Tmod1.
- Abnormal actin bundles, not filament length, cause embryonic lethality in HSPB7 KO mice.
Conclusions:
- HSPB7 is essential for cardiac development, acting as a direct regulator of actin thin filament length.
- HSPB7's inhibition of actin polymerization is critical for sarcomere organization and embryonic survival.
- Aberrant actin bundling, driven by HSPB7 loss, is the primary cause of embryonic lethality in these models.
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.