XBP1 signalling is essential for alleviating mutant protein aggregation in ER-stress related skeletal disease.
Alternative Splicing
Animals
Apoptosis
Cell Proliferation
Cells, Cultured
Chondrocytes
/ cytology
Disease Models, Animal
Endoplasmic Reticulum Stress
Gene Expression Profiling
Humans
Matrilin Proteins
/ chemistry
Mice
Mutation
Osteochondrodysplasias
/ genetics
Protein Aggregates
Signal Transduction
Unfolded Protein Response
X-Box Binding Protein 1
/ genetics
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
07 2019
07 2019
Historique:
received:
24
09
2018
accepted:
27
05
2019
revised:
12
07
2019
pubmed:
2
7
2019
medline:
18
12
2019
entrez:
2
7
2019
Statut:
epublish
Résumé
The unfolded protein response (UPR) is a conserved cellular response to the accumulation of proteinaceous material in endoplasmic reticulum (ER), active both in health and disease to alleviate cellular stress and improve protein folding. Multiple epiphyseal dysplasia (EDM5) is a genetic skeletal condition and a classic example of an intracellular protein aggregation disease, whereby mutant matrilin-3 forms large insoluble aggregates in the ER lumen, resulting in a specific 'disease signature' of increased expression of chaperones and foldases, and alternative splicing of the UPR effector XBP1. Matrilin-3 is expressed exclusively by chondrocytes thereby making EDM5 a perfect model system to study the role of protein aggregation in disease. In order to dissect the role of XBP1 signalling in aggregation-related conditions we crossed a p.V194D Matn3 knock-in mouse model of EDM5 with a mouse line carrying a cartilage specific deletion of XBP1 and analysed the resulting phenotype. Interestingly, the growth of mice carrying the Matn3 p.V194D mutation compounded with the cartilage specific deletion of XBP1 was severely retarded. Further phenotyping revealed increased intracellular retention of amyloid-like aggregates of mutant matrilin-3 coupled with dramatically decreased cell proliferation and increased apoptosis, suggesting a role of XBP1 signalling in protein accumulation and/or degradation. Transcriptomic analysis of chondrocytes extracted from wild type, EDM5, Xbp1-null and compound mutant lines revealed that the alternative splicing of Xbp1 is crucial in modulating levels of protein aggregation. Moreover, through detailed transcriptomic comparison with a model of metaphyseal chondrodysplasia type Schmid (MCDS), an UPR-related skeletal condition in which XBP1 was removed without overt consequences, we show for the first time that the differentiation-state of cells within the cartilage growth plate influences the UPR resulting from retention of a misfolded mutant protein and postulate that modulation of XBP1 signalling pathway presents a therapeutic target for aggregation related conditions in cells undergoing proliferation.
Identifiants
pubmed: 31260448
doi: 10.1371/journal.pgen.1008215
pii: PGENETICS-D-18-01884
pmc: PMC6625722
doi:
Substances chimiques
MATN3 protein, human
0
Matrilin Proteins
0
Protein Aggregates
0
X-Box Binding Protein 1
0
XBP1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008215Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P020941/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 084353/Z/07
Pays : United Kingdom
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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