Fibrillin-1 mgΔlpn Marfan syndrome mutation associates with preserved proteostasis and bypass of a protein disulfide isomerase-dependent quality checkpoint

Meirelles, Thayna; Araujo, Thaís L.S.; Nolasco, Patrícia; Moretti, Ana I.S.; Guido, Maria C.; Debbas, Victor; Pereira, Lygia V.; Laurindo, Francisco R.

doi:10.1016/j.biocel.2015.12.009

Cited by 10Connective tissue disorders researchEndoplasmic Reticulum Stress and DiseaseHeat shock proteins research

Fibrillin-1 mgΔlpn Marfan syndrome mutation associates with preserved proteostasis and bypass of a protein disulfide isomerase-dependent quality checkpoint

Meirelles, Thayna, Araujo, Thaís L.S., Nolasco, Patrícia, Moretti, Ana I.S., Guido, Maria C., Debbas, Victor, Pereira, Lygia V., Laurindo, Francisco R.·2016·The International Journal of Biochemistry & Cell Biology

DOI 10.1016/j.biocel.2015.12.009

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Abstract

Fibrillin-1 mutations promote Marfan syndrome (MFS) via complex yet unclear pathways. The roles of endoplasmic reticulum (ER) and the major ER redox chaperone protein disulfide isomerase-A1 in the processing of normal and mutated fibrillin-1 and ensuing protein secretion and/or intracellular retention are unclear. Our results in mouse embryonic fibroblasts bearing the exon-skipping mgΔ(lox-P-neo) (mgΔ(lpn)) mutation, which associates in vivo with MFS and in vitro with disrupted microfibrils, indicate a preserved ER-dependent proteostasis or redox homeostasis. Rather, mutated fibrillin-1 is secreted normally through Golgi-dependent pathways and is not intracellularly retained. Similar results occurred for the C1039G point mutation. In parallel, we provide evidence that PDIA1 physically interacts with fibrillin-1 in the ER. Moreover, siRNA against PDIA1 augmented fibrillin-1 secretion rates in wild-type cells. However, fibrillin-1 with the mgΔ(lpn) mutation bypassed PDI checkpoint delay, while the C1039G mutation did not. This heretofore undisclosed PDIA1-mediated mechanism may be important to control the extracellular availability of function-competent fibrillin-1, an important determinant of disease phenotype. Moreover, our results may reveal a novel, holdase-like, PDI function associated with ER protein quality control.

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Lack of classical UPR activation (e.g., elevated BiP levels) was previously reported in skin fibroblasts of Osteogenesis imperfecta patients with mutations in triple helical domain of COL1A1, in embryonic fibroblasts from a Marfan syndrome mouse model, and in patients' fibroblasts with different types of mucopolysaccharidoses.
“the lack of a classical UPR activation (e.g., elevated BiP levels) was previously reported in skin fibroblasts of Osteogenesis imperfecta patients with mutations in triple helical domain of COL1A1 [60], as well as in embryonic fibroblasts from a Marfan syndrome mouse model [61] and in patients’ fibroblasts with different types of mucopolysaccharidoses [62]”
From Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome (2018) · cites this paper as [61]

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Authors: Meirelles, T., Araujo, T. L. S., Nolasco, P., Moretti, A. I. S., Guido, M. C., Debbas, V., Pereira, L. V., & Laurindo, F. R.
Affiliations: Universidade de São Paulo (BR)
Corresponding author: Laurindo, Francisco R.
ORCID: Nolasco, Patrícia
Moretti, Ana I.S.
Guido, Maria C.
Pereira, Lygia V.
Laurindo, Francisco R.
Venue: The International Journal of Biochemistry & Cell Biology
Publisher: Elsevier BV
Published: 2016-02
Volume: 71
Pages: 81-91
ISSN: 1357-2725 (ISSN-L)
DOI: 10.1016/j.biocel.2015.12.009
OpenAlex: W2199033532
Cited by: 10
References: 43
Citations by year: 2026: 1 · 2023: 1 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 2
FWCI: 1.37
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: The International Journal of Biochemistry & Cell Biology (publishedVersion)
PubMed (publishedVersion)
Funders: University of Oregon
Fundação de Amparo à Pesquisa do Estado de São Paulo
Universitat de Barcelona
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords: fibrillin-1, Marfan syndrome, protein disulfide isomerase, PDIA1, endoplasmic reticulum proteostasis, protein folding quality control, protein secretion, Golgi apparatus, microfibrils, redox homeostasis, mouse embryonic fibroblasts
MeSH terms: Fibrillins, Fibrillin-1, Animals, Cell Line, Endoplasmic Reticulum, Homeostasis, Marfan Syndrome, Microfilament Proteins, Mutation, Phenotype, Protein Disulfide-Isomerases, Gene Silencing, Microfibrils, Mice, Adipokines

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Fibrillin-1 mgΔlpn Marfan syndrome mutation associates with preserved proteostasis and bypass of a protein disulfide isomerase-dependent quality checkpoint

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