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

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• 作者：Thayna Meirelles^a ; ¹ ; ² ; Thaí ; s L.S. Araujo^a ; ² ; Patrí ; cia Nolasco^a ; Ana I.S. Moretti^a ; Maria C. Guido^a ; Victor Debbas^a ; Lygia V. Pereira^b ; Francisco R. Laurindo^a ; ^{francisco.laurindo@incor.usp.br" class="auth_mail" title="E-mail the corresponding author} ; ^{expfrancisco@incor.usp.br" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Protein disulfide isomerase ; Fibrillin-1 ; Endoplasmic reticulum stress ; Marfan syndrome ; Oxidative folding
• 刊名：International Journal of Biochemistry and Cell Biology
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：71
• 期：Complete
• 页码：81-91
• 全文大小：3279 K

文摘

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.