title: The ER-bound RING finger protein 5 (RNF5/RMA1) causes degenerative myopathy in transgenic mice and is deregulated in inclusion body myositis.
abstract: 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.
authors.affiliation: Signal Transduction, The Burnham Institute for Medical Research, La Jolla, California, USA.
authors.forename: Agnès
authors.initials: A
authors.lastname: Delaunay
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bromberg
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mirabella
authors.forename: Denise
authors.initials: D
authors.lastname: Burch
authors.forename: Brian
authors.initials: B
authors.lastname: Kirkwood
authors.forename: Carlo
authors.initials: C
authors.lastname: Serra
authors.forename: May C
authors.initials: MC
authors.lastname: Malicdan
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Mizisin
authors.forename: Roberta
authors.initials: R
authors.lastname: Morosetti
authors.forename: Aldobrando
authors.initials: A
authors.lastname: Broccolini
authors.forename: Ling T
authors.initials: LT
authors.lastname: Guo
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Jones
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Lira
authors.forename: Pier Lorenzo
authors.initials: PL
authors.lastname: Puri
authors.forename: G Diane
authors.initials: GD
authors.lastname: Shelton
authors.forename: Ze'ev
authors.initials: Z
authors.lastname: Ronai
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins; D015870:Gene Expression; D002479:Inclusion Bodies / Q000737:chemistry / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009135:Muscular Diseases / Q000209:etiology*; D009220:Myositis; D010641:Phenotype; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D008565:Membrane Proteins; C529960:RNF5 protein, mouse; D044767:Ubiquitin-Protein Ligases