LUBAC: a new player in polyglucosan body disease.
Andrew AboujaoudeBerge MinassianSharmistha MitraPublished in: Biochemical Society transactions (2022)
Altered protein ubiquitination is associated with the pathobiology of numerous diseases; however, its involvement in glycogen metabolism and associated polyglucosan body (PB) disease has not been investigated in depth. In PB disease, excessively long and less branched glycogen chains (polyglucosan bodies, PBs) are formed, which precipitate in different tissues causing myopathy, cardiomyopathy and/or neurodegeneration. Linear ubiquitin chain assembly complex (LUBAC) is a multi-protein complex composed of two E3 ubiquitin ligases HOIL-1L and HOIP and an adaptor protein SHARPIN. Together they are responsible for M1-linked ubiquitination of substrates primarily related to immune signaling and cell death pathways. Consequently, severe immunodeficiency is a hallmark of many LUBAC deficient patients. Remarkably, all HOIL-1L deficient patients exhibit accumulation of PBs in different organs especially skeletal and cardiac muscle resulting in myopathy and cardiomyopathy with heart failure. This emphasizes LUBAC's important role in glycogen metabolism. To date, neither a glycogen metabolism-related LUBAC substrate nor the molecular mechanism are known. Hence, current reviews on LUBAC's involvement in glycogen metabolism are lacking. Here, we aim to fill this gap by describing LUBAC's involvement in PB disease. We present a comprehensive review of LUBAC structure, its role in M1-linked and other types of atypical ubiquitination, PB pathology in human patients and findings in new mouse models to study the disease. We conclude the review with recent drug developments and near-future gene-based therapeutic approaches to treat LUBAC related PB disease.
Keyphrases
- end stage renal disease
- heart failure
- chronic kidney disease
- ejection fraction
- cell death
- newly diagnosed
- heavy metals
- peritoneal dialysis
- randomized controlled trial
- gene expression
- endothelial cells
- amino acid
- left ventricular
- dna methylation
- cell proliferation
- late onset
- transcription factor
- genome wide
- mass spectrometry
- binding protein
- optical coherence tomography
- drug induced
- acute heart failure
- neural network