title: Fibrillin-1 mgΔ(lpn) Marfan syndrome mutation associates with preserved proteostasis and bypass of a protein disulfide isomerase-dependent quality checkpoint.
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.
authors.affiliation: Vascular Biology Laboratory, Heart Institute (InCor), School of Medicine, University of São Paulo, Av. Enéas Carvalho Aguiar, 44, Annex II, 9th Floor, 05403-000 São Paulo, Brazil.
authors.forename: Thayna
authors.initials: T
authors.lastname: Meirelles
authors.affiliation: Vascular Biology Laboratory, Heart Institute (InCor), School of Medicine, University of São Paulo, Av. Enéas Carvalho Aguiar, 44, Annex II, 9th Floor, 05403-000 São Paulo, Brazil.
authors.forename: Thaís L S
authors.initials: TLS
authors.lastname: Araujo
authors.affiliation: Vascular Biology Laboratory, Heart Institute (InCor), School of Medicine, University of São Paulo, Av. Enéas Carvalho Aguiar, 44, Annex II, 9th Floor, 05403-000 São Paulo, Brazil.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Nolasco
authors.affiliation: Vascular Biology Laboratory, Heart Institute (InCor), School of Medicine, University of São Paulo, Av. Enéas Carvalho Aguiar, 44, Annex II, 9th Floor, 05403-000 São Paulo, Brazil.
authors.forename: Ana I S
authors.initials: AIS
authors.lastname: Moretti
authors.affiliation: Vascular Biology Laboratory, Heart Institute (InCor), School of Medicine, University of São Paulo, Av. Enéas Carvalho Aguiar, 44, Annex II, 9th Floor, 05403-000 São Paulo, Brazil.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Guido
authors.affiliation: Vascular Biology Laboratory, Heart Institute (InCor), School of Medicine, University of São Paulo, Av. Enéas Carvalho Aguiar, 44, Annex II, 9th Floor, 05403-000 São Paulo, Brazil.
authors.forename: Victor
authors.initials: V
authors.lastname: Debbas
authors.affiliation: Laboratory of Molecular Genetics, Department of Genetics and Evolutionary Biology, University of São Paulo, São Paulo, Brazil.
authors.forename: Lygia V
authors.initials: LV
authors.lastname: Pereira
authors.affiliation: Vascular Biology Laboratory, Heart Institute (InCor), School of Medicine, University of São Paulo, Av. Enéas Carvalho Aguiar, 44, Annex II, 9th Floor, 05403-000 São Paulo, Brazil. Electronic address: francisco.laurindo@incor.usp.br.
authors.forename: Francisco R
authors.initials: FR
authors.lastname: Laurindo
mesh_terms: D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000071838:Fibrillin-1; D000071837:Fibrillins; D020868:Gene Silencing; D006706:Homeostasis / Q000235:genetics*; D008382:Marfan Syndrome / Q000235:genetics*; D051379:Mice; D020894:Microfibrils / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D019704:Protein Disulfide-Isomerases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D019704:Protein Disulfide-Isomerases; C000605724:Fbn1 protein, mouse; D054392:Adipokines
keywords: Endoplasmic reticulum stress; Fibrillin-1; Marfan syndrome; Oxidative folding; Protein disulfide isomerase