CYLD dysregulation in pathogenesis of sporadic inclusion body myositis

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.

Five-Lipoxygenase-Activating Protein Mediated CYLD Attenuation is a Candidate Driver in Hepatic Malignant Lesion

“…Although high expression of CysLTR2 appears in resection tissues of HCC patients and in AAI-induced premalignant livers of canines, the data from both HepG2 lv−FLAP and HepG2 sh−FLAP cells do not demonstrate the impact of FLAP abundance on CysLTR2 expression. We therefore focus on the hepatic ER stress/CysLTRs axis as ER stress triggers CysLTRs internalization [14] and ER stress inducers show the ability to reduce CYLD expression [33]. Our data demonstrate that AAI treatment triggers the early and late events of ER stress in canine livers, as evidenced by high Grp78 expression and of eIF2α phosphorylation, thereby promoting CysLTR2 internalization.…”

“…To understand the underlying molecular mechanism of CysLTs-associated with CYLD attenuation after AAI treatment, we subsequently focused on the connection of CysLTs/CysLTRs signaling in canine livers. Meanwhile, we also checked endoplasmic reticulum (ER) stress, since ER stress inducers showed the ability to reduce CYLD expression [33]. We detected the expressions of CysLTR1, CysLTR2, BLT1 (the higha nity receptor of LTB 4 ), BLT2, Grp78, Grp 94 (the early events of ER stress), as well as phosphorylation of eIF2α (the late event of ER stress) once stimulated with AAI.…”

Cell environment shapes TDP-43 function: implications in neuronal and muscle disease

“…To this date, cell-and tissue-characteristic molecular features of TDP-43 have seldom been investigated in parallel. Considering recent attention that TDP-43 has received in IBM and related pathologies (Harms et al, 2012;Salajegheh et al, 2009;Weihl et al, 2008;Yamashita et al, 2019), we therefore sought to fill this gap. The purpose of our study has been to further explicate the role of TDP-43 in different tissues to better understand its involvement in pathogenesis in cell types other than neurons, and to set the ground for development of potential therapeutic or biomarker strategies that focus on shared or specific disease mechanisms.…”

Rare CYLD Variants in Chinese Patients With Amyotrophic Lateral Sclerosis

“…CYLD is a deubiquitinating enzyme that targets Lys63-linked ubiquitin chains and regulates biological pathways such as the NF-ĸB signaling pathway and autophagy ( Kovalenko et al, 2003 ; Yamashita et al, 2019 ). Loss-of-function mutations in CYLD have been shown to cause skin diseases, while very recently, missense mutations in CYLD were found to cause ALS-FTD via gain-of-function mechanism ( Dobson-stone et al, 2020 ).…”