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MBC in Press, published online ahead of print November 12, 2008
Mol. Biol. Cell 10.1091/mbc.E08-07-0753

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Submitted on July 23, 2008
Revised on October 14, 2008
Accepted on October 30, 2008

A Myopathy-linked Desmin Mutation Perturbs Striated Muscle Actin Filament Architecture

Gloria M. Conover,* Syerra N. Henderson,{dagger} and Carol C. Gregorio

Department of Cell Biology and Anatomy, University of Arizona, Tucson, AZ 85724

Monitoring Editor: Robert G. Parton

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, while 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 since 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.

*Present address: College of Veterinary Medicine, Department of Veterinary Pathobiology, Texas A&M University, College Station, TX 77843.

{dagger}Present name and address: Syerra N. Lea, Midwestern University, Glendale, AZ 85308.

Address correspondence to: Carol C. Gregorio (gregorio{at}u.arizona.edu)






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