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

Author(s)

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]

Affiliation

^[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

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY; v. 71, p. 81-91, FEB 2016.
• Web of Science Citations: 5

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 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 Opportunities: Scholarships abroad - Research Internship - Doctorate
• 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 Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC