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LUBAC: a new player in polyglucosan body disease
- Source :
- Biochemical Society Transactions
- Publication Year :
- 2021
- Publisher :
- Portland Press Ltd., 2021.
-
Abstract
- 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.
- Subjects :
- HOIP
Cardiomyopathy
Biochemistry
Molecular Bases of Health & Disease
chemistry.chemical_compound
ubiquitin ligases
Mice
Ubiquitin
LUBAC
medicine
Animals
Humans
Myopathy
HOIL-1L
Review Articles
Glucans
Immunodeficiency
Post-Translational Modifications
Glycogen
biology
Molecular Interactions
Molecular Structure
Neurodegeneration
Ubiquitination
Signal transducing adaptor protein
M1 ubiquitination
medicine.disease
Therapeutics & Molecular Medicine
gene therapy
Protein ubiquitination
Cell biology
Metabolism
chemistry
biology.protein
medicine.symptom
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 14708752 and 03005127
- Volume :
- 49
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Biochemical Society Transactions
- Accession number :
- edsair.doi.dedup.....71d0d444d4a72ab54ff426a0cdcfcfca