The ER-bound RING finger protein 5 (RNF5/RMA1) causes degenerative myopathy in transgenic mice and is deregulated in inclusion body myositis
Authors
Delaunay, AgnesBromberg, Kenneth D.
Hayashi, Yukiko
Mirabella, Massimiliano
Burch, Denise
Kirkwood, Brian
Serra, Carlo
Malicdan, May C.
Mizisin, Andrew P.
Morosetti, Roberta
Broccolini, Aldobrando
Guo, Ling T.
Jones, Stephen N.
Lira, Sergio A.
Puri, Pier Lorenzo
Shelton, G. Diane
Ronai, Ze'ev
UMass Chan Affiliations
Department of Cell BiologyDocument Type
Journal ArticlePublication Date
2008-02-14Keywords
AnimalsDNA-Binding Proteins
Gene Expression
Inclusion Bodies
Membrane Proteins
Mice
Mice, Transgenic
Muscular Diseases
*Myositis
Phenotype
Ubiquitin-Protein Ligases
Cell Biology
Metadata
Show full item recordAbstract
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.Source
PLoS One. 2008 Feb 13;3(2):e1609. Link to article on publisher's siteDOI
10.1371/journal.pone.0001609Permanent Link to this Item
http://hdl.handle.net/20.500.14038/36012Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0001609