title: Inhibition of Coxsackievirus-associated dystrophin cleavage prevents cardiomyopathy.
abstract: Heart failure in children and adults is often the consequence of myocarditis associated with Coxsackievirus (CV) infection. Upon CV infection, enteroviral protease 2A cleaves a small number of host proteins including dystrophin, which links actin filaments to the plasma membrane of muscle fiber cells (sarcolemma). It is unknown whether protease 2A-mediated cleavage of dystrophin and subsequent disruption of the sarcolemma play a role in CV-mediated myocarditis. We generated knockin mice harboring a mutation at the protease 2A cleavage site of the dystrophin gene, which prevents dystrophin cleavage following CV infection. Compared with wild-type mice, we found that mice expressing cleavage-resistant dystrophin had a decrease in sarcolemmal disruption and cardiac virus titer following CV infection. In addition, cleavage-resistant dystrophin inhibited the cardiomyopathy induced by cardiomyocyte-restricted expression of the CV protease 2A transgene. These findings indicate that protease 2A-mediated cleavage of dystrophin is critical for viral propagation, enteroviral-mediated cytopathic effects, and the development of cardiomyopathy.
authors.forename: Byung-Kwan
authors.initials: BK
authors.lastname: Lim
authors.forename: Angela K
authors.initials: AK
authors.lastname: Peter
authors.forename: Dingding
authors.initials: D
authors.lastname: Xiong
authors.forename: Anna
authors.initials: A
authors.lastname: Narezkina
authors.forename: Aaron
authors.initials: A
authors.lastname: Yung
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Dalton
authors.forename: Kyung-Kuk
authors.initials: KK
authors.lastname: Hwang
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Yajima
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.forename: Kirk U
authors.initials: KU
authors.lastname: Knowlton
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003384:Coxsackievirus Infections / Q000378:metabolism / Q000517:prevention & control* / Q000821:virology; D003546:Cysteine Endopeptidases / Q000502:physiology*; D003588:Cytopathogenic Effect, Viral; D016189:Dystrophin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D029822:Enterovirus B, Human / Q000201:enzymology* / Q000502:physiology; D055879:Gene Knock-In Techniques; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009154:Mutation; D009205:Myocarditis / Q000378:metabolism / Q000517:prevention & control* / Q000821:virology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000821:virology; D059748:Proteolysis; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012508:Sarcolemma / Q000473:pathology; D019076:Transgenes; D014764:Viral Proteins / Q000502:physiology*; D014779:Virus Replication
chemical_list: D016189:Dystrophin; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; C085339:apo-dystrophin 1; D003546:Cysteine Endopeptidases; C057400:picornain 2A, Picornavirus