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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Fibrillin-1 mg Delta(lPn) Marfan syndrome mutation associates with preserved proteostasis and bypass of a protein disulfide isomerase-dependent quality checkpoint

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Meirelles, Thayna [1, 2] ; Araujo, Thais L. S. [1] ; Nolasco, Patricia [1] ; Moretti, Ana I. S. [1] ; Guido, Maria C. [1] ; Debbas, Victor [1] ; Pereira, Lygia V. [3] ; Laurindo, Francisco R. [1]
Total Authors: 8
[1] Univ Sao Paulo, Sch Med, Heart Inst InCor, Vasc Biol Lab, Ave Eneas Carvalho Aguiar 44, Annex 2, BR-05403000 Sao Paulo - Brazil
[2] Univ Barcelona, Fac Med, Dept Biol Cellular Immunol & Neurociencies, IDIBAPS, C Casanova 143, Barcelona 08036 - Spain
[3] Univ Sao Paulo, Dept Genet & Evolutionary Biol, Mol Genet Lab, BR-05403000 Sao Paulo - Brazil
Total Affiliations: 3
Document type: Journal article
Web of Science Citations: 5

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 mg Delta(lox-p-neo) (mg Delta(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 mg Delta(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. (C) 2015 Elsevier Ltd. All rights reserved. (AU)

FAPESP's process: 12/23490-0 - Functional role of NADPH oxidase isoform 4 (Nox4) in Marfan Syndrome
Grantee:Thayna Meirelles Santos
Support type: Scholarships abroad - Research Internship - Doctorate
FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
Grantee:Ohara Augusto
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 09/54764-6 - Regulation of redox homeostasis and integrated stress response by Protein Disulfide Isomerase (PDI): mechanisms and role in the pathophysiology and therapy of vascular diseases
Grantee:Francisco Rafael Martins Laurindo
Support type: Research Projects - Thematic Grants