TY - JOUR
T1 - Mutant MESD links cellular stress to type I collagen aggregation in osteogenesis imperfecta type XX
AU - Ghosh, Debasish Kumar
AU - Udupa, Prajna
AU - Shrikondawar, Akshaykumar Nanaji
AU - Bhavani, Gandham Sri Lakshmi
AU - Shah, Hitesh
AU - Ranjan, Akash
AU - Girisha, Katta M.
N1 - Publisher Copyright:
© 2022 Elsevier B.V.
PY - 2023/1/1
Y1 - 2023/1/1
N2 - Aberrant forms of endoplasmic reticulum (ER)-resident chaperones are implicated in loss of protein quality control in rare diseases. Here we report a novel mutation (p.Asp233Asn) in the ER retention signal of MESD by whole exome sequencing of an individual diagnosed with osteogenesis imperfecta (OI) type XX. While MESDD233N has similar stability and chaperone activity as wild-type MESD, its mislocalization to cytoplasm leads to imbalance of ER proteostasis, resulting in improper folding and aggregation of proteins, including LRP5 and type I collagen. Aggregated LRP5 loses its plasma membrane localization to disrupt the expression of WNT-responsive genes, such as BMP2, BMP4, in proband fibroblasts. We show that MESD is a direct chaperone of pro-α1(I) [COL1A1], and absence of MESDD233N in ER results in cytosolic type I collagen aggregates that remain mostly not secreted. While cytosolic type I collagen aggregates block the intercellular nanotubes, decreased extracellular type I collagen also results in loss of interaction of ITGB1 with type I collagen and weaker attachment of fibroblasts to matrix. Although proband fibroblasts show increased autophagy to degrade the aggregated type I collagen, an overall cellular stress overwhelms the proband fibroblasts. In summary, we present an essential chaperone function of MESD for LRP5 and type I collagen and demonstrating how the D233N mutation in MESD correlates with impaired WNT signaling and proteostasis in OI.
AB - Aberrant forms of endoplasmic reticulum (ER)-resident chaperones are implicated in loss of protein quality control in rare diseases. Here we report a novel mutation (p.Asp233Asn) in the ER retention signal of MESD by whole exome sequencing of an individual diagnosed with osteogenesis imperfecta (OI) type XX. While MESDD233N has similar stability and chaperone activity as wild-type MESD, its mislocalization to cytoplasm leads to imbalance of ER proteostasis, resulting in improper folding and aggregation of proteins, including LRP5 and type I collagen. Aggregated LRP5 loses its plasma membrane localization to disrupt the expression of WNT-responsive genes, such as BMP2, BMP4, in proband fibroblasts. We show that MESD is a direct chaperone of pro-α1(I) [COL1A1], and absence of MESDD233N in ER results in cytosolic type I collagen aggregates that remain mostly not secreted. While cytosolic type I collagen aggregates block the intercellular nanotubes, decreased extracellular type I collagen also results in loss of interaction of ITGB1 with type I collagen and weaker attachment of fibroblasts to matrix. Although proband fibroblasts show increased autophagy to degrade the aggregated type I collagen, an overall cellular stress overwhelms the proband fibroblasts. In summary, we present an essential chaperone function of MESD for LRP5 and type I collagen and demonstrating how the D233N mutation in MESD correlates with impaired WNT signaling and proteostasis in OI.
KW - Autophagy
KW - MESD
KW - Osteogenesis imperfecta
KW - Protein aggregation
KW - Proteostasis imbalance
KW - Type I collagen
KW - Collagen Type I/genetics
KW - Osteogenesis Imperfecta/genetics
KW - Humans
KW - Cell Membrane/metabolism
KW - Mutation
KW - Molecular Chaperones/genetics
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U2 - 10.1016/j.matbio.2022.12.001
DO - 10.1016/j.matbio.2022.12.001
M3 - Article
C2 - 36526215
AN - SCOPUS:85144312182
SN - 0945-053X
VL - 115
SP - 81
EP - 106
JO - Matrix Biology
JF - Matrix Biology
ER -