A myopathy-linked desmin mutation perturbs striated muscle actin filament architecture

Gloria M. Conover, Syerra N. Henderson, Carol Gregorio

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Desmin interacts with nebulin establishing a direct link between the intermediate filament network and sarcomeres at the Z-discs. Here, we examined a desmin mutation, E245D, that is located within the coil IB (nebulin-binding) region of desmin and that has been reported to cause human cardiomyopathy and skeletal muscle atrophy. We show that the coil IB region of desmin binds to C-terminal nebulin (modules 160-164) with high affinity, whereas binding of this desmin region containing the E245D mutation appears to enhance its interaction with nebulin in solid-phase binding assays. Expression of the desmin-E245D mutant in myocytes displaces endogenous desmin and C-terminal nebulin from the Z-discs with a concomitant increase in the formation of intracellular aggregates, reminiscent of a major histological hallmark of desmin-related myopathies. Actin filament architecture was strikingly perturbed in myocytes expressing the desmin-E245D mutant because most sarcomeres contained elongated or shorter actin filaments. Our findings reveal a novel role for desmin intermediate filaments in modulating actin filament lengths and organization. Collectively, these data suggest that the desmin E245D mutation interferes with the ability of nebulin to precisely regulate thin filament lengths, providing new insights into the potential molecular consequences of expression of certain disease-associated desmin mutations.

Original languageEnglish (US)
Pages (from-to)834-845
Number of pages12
JournalMolecular Biology of the Cell
Volume20
Issue number3
DOIs
StatePublished - Jan 1 2009

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Desmin
Striated Muscle
Muscular Diseases
Actin Cytoskeleton
Mutation
Sarcomeres
Intermediate Filaments
Muscle Cells
Muscular Atrophy
Cardiomyopathies
nebulin
Skeletal Muscle

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

A myopathy-linked desmin mutation perturbs striated muscle actin filament architecture. / Conover, Gloria M.; Henderson, Syerra N.; Gregorio, Carol.

In: Molecular Biology of the Cell, Vol. 20, No. 3, 01.01.2009, p. 834-845.

Research output: Contribution to journalArticle

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