Show simple item record

dc.contributor.authorDelaunay, Agnes
dc.contributor.authorBromberg, Kenneth D.
dc.contributor.authorHayashi, Yukiko
dc.contributor.authorMirabella, Massimiliano
dc.contributor.authorBurch, Denise
dc.contributor.authorKirkwood, Brian
dc.contributor.authorSerra, Carlo
dc.contributor.authorMalicdan, May C.
dc.contributor.authorMizisin, Andrew P.
dc.contributor.authorMorosetti, Roberta
dc.contributor.authorBroccolini, Aldobrando
dc.contributor.authorGuo, Ling T.
dc.contributor.authorJones, Stephen N.
dc.contributor.authorLira, Sergio A.
dc.contributor.authorPuri, Pier Lorenzo
dc.contributor.authorShelton, G. Diane
dc.contributor.authorRonai, Ze'ev
dc.date2022-08-11T08:09:15.000
dc.date.accessioned2022-08-23T16:23:56Z
dc.date.available2022-08-23T16:23:56Z
dc.date.issued2008-02-14
dc.date.submitted2011-01-28
dc.identifier.citationPLoS One. 2008 Feb 13;3(2):e1609. <a href="http://dx.doi.org/10.1371/journal.pone.0001609">Link to article on publisher's site</a>
dc.identifier.issn1932-6203 (Electronic)
dc.identifier.doi10.1371/journal.pone.0001609
dc.identifier.urihttp://hdl.handle.net/20.500.14038/36012
dc.description.abstractGrowing evidence supports the importance of ubiquitin ligases in the pathogenesis of muscular disorders, although underlying mechanisms remain largely elusive. Here we show that the expression of RNF5 (aka RMA1), an ER-anchored RING finger E3 ligase implicated in muscle organization and in recognition and processing of malfolded proteins, is elevated and mislocalized to cytoplasmic aggregates in biopsies from patients suffering from sporadic-Inclusion Body Myositis (sIBM). Consistent with these findings, an animal model for hereditary IBM (hIBM), but not their control littermates, revealed deregulated expression of RNF5. Further studies for the role of RNF5 in the pathogenesis of s-IBM and more generally in muscle physiology were performed using RNF5 transgenic and KO animals. Transgenic mice carrying inducible expression of RNF5, under control of beta-actin or muscle specific promoter, exhibit an early onset of muscle wasting, muscle degeneration and extensive fiber regeneration. Prolonged expression of RNF5 in the muscle also results in the formation of fibers containing congophilic material, blue-rimmed vacuoles and inclusion bodies. These phenotypes were associated with altered expression and activity of ER chaperones, characteristic of myodegenerative diseases such as s-IBM. Conversely, muscle regeneration and induction of ER stress markers were delayed in RNF5 KO mice subjected to cardiotoxin treatment. While supporting a role for RNF5 Tg mice as model for s-IBM, our study also establishes the importance of RNF5 in muscle physiology and its deregulation in ER stress associated muscular disorders.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=18270596&dopt=Abstract">Link to Article in PubMed</a>
dc.subjectAnimals
dc.subjectDNA-Binding Proteins
dc.subjectGene Expression
dc.subjectInclusion Bodies
dc.subjectMembrane Proteins
dc.subjectMice
dc.subjectMice, Transgenic
dc.subjectMuscular Diseases
dc.subject*Myositis
dc.subjectPhenotype
dc.subjectUbiquitin-Protein Ligases
dc.subjectCell Biology
dc.titleThe ER-bound RING finger protein 5 (RNF5/RMA1) causes degenerative myopathy in transgenic mice and is deregulated in inclusion body myositis
dc.typeJournal Article
dc.source.journaltitlePloS one
dc.source.volume3
dc.source.issue2
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1015&amp;context=jones&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/jones/16
dc.identifier.contextkey1750949
refterms.dateFOA2022-08-23T16:23:56Z
html.description.abstract<p>Growing evidence supports the importance of ubiquitin ligases in the pathogenesis of muscular disorders, although underlying mechanisms remain largely elusive. Here we show that the expression of RNF5 (aka RMA1), an ER-anchored RING finger E3 ligase implicated in muscle organization and in recognition and processing of malfolded proteins, is elevated and mislocalized to cytoplasmic aggregates in biopsies from patients suffering from sporadic-Inclusion Body Myositis (sIBM). Consistent with these findings, an animal model for hereditary IBM (hIBM), but not their control littermates, revealed deregulated expression of RNF5. Further studies for the role of RNF5 in the pathogenesis of s-IBM and more generally in muscle physiology were performed using RNF5 transgenic and KO animals. Transgenic mice carrying inducible expression of RNF5, under control of beta-actin or muscle specific promoter, exhibit an early onset of muscle wasting, muscle degeneration and extensive fiber regeneration. Prolonged expression of RNF5 in the muscle also results in the formation of fibers containing congophilic material, blue-rimmed vacuoles and inclusion bodies. These phenotypes were associated with altered expression and activity of ER chaperones, characteristic of myodegenerative diseases such as s-IBM. Conversely, muscle regeneration and induction of ER stress markers were delayed in RNF5 KO mice subjected to cardiotoxin treatment. While supporting a role for RNF5 Tg mice as model for s-IBM, our study also establishes the importance of RNF5 in muscle physiology and its deregulation in ER stress associated muscular disorders.</p>
dc.identifier.submissionpathjones/16
dc.contributor.departmentDepartment of Cell Biology
dc.source.pagese1609


Files in this item

Thumbnail
Name:
journal.pone.0001609.pdf
Size:
4.965Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record