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Cardiac myofibrillogenesis is spatiotemporally modulated by the molecular chaperone UNC45B

Serena Huei-An Lu1, Yi-Hsuan Wu1, Liang-Yu Su1

  • 1Department of Life Science, National Taiwan University, Taipei 10617, Taiwan.

Stem Cell Reports
|June 9, 2023
PubMed

Insights

The molecular chaperone UNC45B is crucial for cardiac muscle contraction, regulating sarcomere assembly by controlling protocostamere formation and protein interactions. Its absence severely impairs cardiomyocyte contractility and myofibrillogenesis.

Area of Science:

  • Cardiovascular Biology
  • Muscle Physiology
  • Stem Cell Biology

Background:

  • Sarcomere dysfunction underlies cardiomyopathies, a major global health concern.
  • The precise molecular mechanisms governing sarcomere assembly in cardiomyocytes are not fully understood.

Purpose of the Study:

  • To elucidate the spatiotemporal regulation of proteins involved in cardiac myofibrillogenesis.
  • To investigate the role of the molecular chaperone UNC45B in sarcomere formation and cardiomyocyte function.

Main Methods:

  • Utilized human embryonic stem cell (hESC)-derived cardiomyocytes (CMs).
  • Performed UNC45B-knockout experiments and phenotypic analyses.
  • Examined protein co-expression, distribution, and interactions (e.g., UNC45B, KINDLIN2, MYH6, ACTN2, F-ACTIN).

Main Results:

  • UNC45B is co-expressed with KINDLIN2 (protocostamere marker) and later overlaps with MYH6.
  • UNC45B-knockout CMs exhibit a complete loss of contractility.
  • Impaired protocostamere formation disrupts ACTN2 binding, suppresses F-ACTIN polymerization, and leads to MYH6 degradation.

Conclusions:

  • UNC45B is essential for cardiac myofibrillogenesis, mediating protocostamere formation via KIND2 regulation.
  • UNC45B's spatiotemporal interactions are critical for proper sarcomere assembly and cardiomyocyte function.
  • Understanding UNC45B's role offers insights into cardiomyopathies and potential therapeutic targets.

Keywords:
CRISPR/Cas9 techniqueSarcomerecardiac myofibrillogenesiscardiomyocytemolecular chaperoneprotocostamere

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