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Enteroviral protease 2A cleaves dystrophin: Evidence of cytoskeletal disruption in an acquired cardiomyopathy

Nature Medicine volume 5, pages 320–326 (1999)Cite this article

Abstract

Enteroviruses such as Coxsackievirus B3 can cause dilated cardiomyopathy, but the mechanism of this pathology is unknown. Mutations in cytoskeletal proteins such as dystrophin cause hereditary dilated cardiomyopathy, but it is unclear if similar mechanisms underlie acquired forms of heart failure. We demonstrate here that purified Coxsackievirus protease 2A cleaves dystrophin in vitro as predicted by computer analysis. Dystrophin is also cleaved during Coxsackievirus infection of cultured myocytes and in infected mouse hearts, leading to impaired dystrophin function. In vivo, dystrophin and the dystrophin-associated glycoproteins α-sarcoglycan and β-dystroglycan are morphologically disrupted in infected myocytes. We suggest a molecular mechanism through which enteroviral infection contributes to the pathogenesis of acquired forms of dilated cardiomyopathy.

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Figure 1: Cleavage of dystrophin by Coxsackievirus protease 2A.
Figure 2: Dystrophin and eIF4G-1 are cleaved during Coxsackievirus B3 infection of cultured myocytes.
Figure 3: Dystrophin is cleaved during Coxsackievirus B3 infection in vivo in SCID and immunocompetent mice.
Figure 4: The sarcolemmal integrity is impaired and dystrophin, α-sarcoglycan and β-dystroglycan staining is disrupted in infected myocytes from SCID mice.
Figure 5: A model for the role of dystrophin in Coxsackievirus-induced dilated cardiomyopathy.

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Acknowledgements

Antibody MF20, developed by D.A. Fishman and colleagues, was obtained from the Developmental Studies Hybridoma Bank maintained by the University of Iowa Department of Biological Sciences (Iowa City, Iowa 52242, USA) under contract NO1-HD-7-3263 from the NICHD. Suang Huang provided assistance with the adenovirus experiments. This work was supported by grant Ba 1668/1-1 from the Deutsche Forschungsgemeinschaft to C.B.; grants from the American Heart Association (96-306A) and UCSD Biotechnology Star Project (S96-38) to K.U.K.; and grant GM20818 from the NIH to R.E.R. K.P.C. is an Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Medicine, University of California, San Diego, 92093, California, USA

    Cornel Badorff, Gil-Hwan Lee & Kirk U. Knowlton

  2. Department of Biochemistry and Molecular Biology, Louisiana State University Medical Center, Shreveport, 71130-3932, Louisiana, USA

    Barry J. Lamphear & Robert E. Rhoads

  3. Department of Neurosciences, National Center for Microscopy and Imaging Research, University of California, San Diego, 92093, California, USA

    Maryann E. Martone

  4. Department of Physiology and Biophysics, Department of Neurology, Howard Hughes Medical Institute, University of Iowa College of Medicine, Iowa City, 52242, Iowa, USA

    Kevin P. Campbell

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Correspondence to Kirk U. Knowlton.

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Badorff, C., Lee, GH., Lamphear, B. et al. Enteroviral protease 2A cleaves dystrophin: Evidence of cytoskeletal disruption in an acquired cardiomyopathy. Nat Med 5, 320–326 (1999). https://doi.org/10.1038/6543

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