RRC ID 58005
著者 Yamashita S, Matsuo Y, Tawara N, Hara K, Yamamoto M, Nishikami T, Kawakami K, Zhang X, Zhang Z, Doki T, Ando Y.
タイトル CYLD dysregulation in pathogenesis of sporadic inclusion body myositis.
ジャーナル Sci Rep
Abstract Sporadic inclusion body myositis (sIBM) is the most commonly acquired myopathy in middle-aged and elderly people. The muscle histology is characterized by both inflammation and degeneration, including sarcoplasmic aggregation of TDP-43. Cylindromatosis (CYLD) is a deubiquitinating enzyme that targets Lys63-linked ubiquitin chains and negatively regulates signal transduction pathways, such as NF-κB signalling pathways. We examined localization of CYLD as well as phosphorylated TDP-43, phosphorylated p62, and Lys63-linked ubiquitin in muscle tissues of sIBM patients and muscle-specific wild-type TDP-43 transgenic (TDP-43 TG) mice. We investigated whether overexpression of CYLD can affect muscle toxicity in the cell models treated by endoplasmic reticulum (ER) stress inducers tunicamycin and thapsigargin. CYLD expressed with phosphorylated TDP-43, phosphorylated p62, and Lys63-linked ubiquitin in the nuclear and perinuclear regions of muscle fibres of wild-type TDP-43 TG mice and the degenerative myofibres of sIBM patients with rimmed vacuoles and endomysial cellular infiltration. Although expression levels of CYLD decreased and cell viability was reduced in cells treated with ER stress inducers, wild-type CYLD, but not the catalytic mutant, substantially improved cell viability based on the deubiquitinase activity. Dysregulation of CYLD may reinforce myodegeneration in the pathophysiology of sIBM by attenuating autophagic clearance of protein aggregates. Regulating CYLD in muscle fibres might serve as a novel therapeutic strategy for sIBM treatment.
巻・号 9(1)
ページ 11606
公開日 2019-8-12
DOI 10.1038/s41598-019-48115-2
PII 10.1038/s41598-019-48115-2
PMID 31406156
PMC PMC6690995
MeSH Aged Animals Deubiquitinating Enzyme CYLD / genetics Deubiquitinating Enzyme CYLD / physiology* Endoplasmic Reticulum Stress Humans Mice Mice, Transgenic Middle Aged Myositis, Inclusion Body / metabolism Myositis, Inclusion Body / physiopathology* Phosphorylation Proteomics Ubiquitin / metabolism Vacuoles / metabolism
IF 3.998
引用数 0
リソース情報
ヒト・動物細胞 C2C12(RCB0987)