Chemical chaperones improve protein secretion and rescue mutant factor VIII in mice with hemophilia A.

Inefficient intracellular protein trafficking is a critical issue in the pathogenesis of a variety of diseases and in recombinant protein production. Here we investigated the trafficking of factor VIII (FVIII), which is affected in the coagulation disorder hemophilia A. We hypothesized that chemical...

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Autores principales:	Stefanie D Roth, Jörg Schüttrumpf, Peter Milanov, Daniela Abriss, Christopher Ungerer, Patricia Quade-Lyssy, Jeremy C Simpson, Rainer Pepperkok, Erhard Seifried, Torsten Tonn
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c3ff58452a9c4d699c82179d32d05aaf
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spelling	oai:doaj.org-article:c3ff58452a9c4d699c82179d32d05aaf2021-11-18T07:06:40ZChemical chaperones improve protein secretion and rescue mutant factor VIII in mice with hemophilia A.1932-620310.1371/journal.pone.0044505https://doaj.org/article/c3ff58452a9c4d699c82179d32d05aaf2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22973456/?tool=EBIhttps://doaj.org/toc/1932-6203Inefficient intracellular protein trafficking is a critical issue in the pathogenesis of a variety of diseases and in recombinant protein production. Here we investigated the trafficking of factor VIII (FVIII), which is affected in the coagulation disorder hemophilia A. We hypothesized that chemical chaperones may be useful to enhance folding and processing of FVIII in recombinant protein production, and as a therapeutic approach in patients with impaired FVIII secretion. A tagged B-domain-deleted version of human FVIII was expressed in cultured Chinese Hamster Ovary cells to mimic the industrial production of this important protein. Of several chemical chaperones tested, the addition of betaine resulted in increased secretion of FVIII, by increasing solubility of intracellular FVIII aggregates and improving transport from endoplasmic reticulum to Golgi. Similar results were obtained in experiments monitoring recombinant full-length FVIII. Oral betaine administration also increased FVIII and factor IX (FIX) plasma levels in FVIII or FIX knockout mice following gene transfer. Moreover, in vitro and in vivo applications of betaine were also able to rescue a trafficking-defective FVIII mutant (FVIIIQ305P). We conclude that chemical chaperones such as betaine might represent a useful treatment concept for hemophilia and other diseases caused by deficient intracellular protein trafficking.Stefanie D RothJörg SchüttrumpfPeter MilanovDaniela AbrissChristopher UngererPatricia Quade-LyssyJeremy C SimpsonRainer PepperkokErhard SeifriedTorsten TonnPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 9, p e44505 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Stefanie D Roth Jörg Schüttrumpf Peter Milanov Daniela Abriss Christopher Ungerer Patricia Quade-Lyssy Jeremy C Simpson Rainer Pepperkok Erhard Seifried Torsten Tonn Chemical chaperones improve protein secretion and rescue mutant factor VIII in mice with hemophilia A.
description	Inefficient intracellular protein trafficking is a critical issue in the pathogenesis of a variety of diseases and in recombinant protein production. Here we investigated the trafficking of factor VIII (FVIII), which is affected in the coagulation disorder hemophilia A. We hypothesized that chemical chaperones may be useful to enhance folding and processing of FVIII in recombinant protein production, and as a therapeutic approach in patients with impaired FVIII secretion. A tagged B-domain-deleted version of human FVIII was expressed in cultured Chinese Hamster Ovary cells to mimic the industrial production of this important protein. Of several chemical chaperones tested, the addition of betaine resulted in increased secretion of FVIII, by increasing solubility of intracellular FVIII aggregates and improving transport from endoplasmic reticulum to Golgi. Similar results were obtained in experiments monitoring recombinant full-length FVIII. Oral betaine administration also increased FVIII and factor IX (FIX) plasma levels in FVIII or FIX knockout mice following gene transfer. Moreover, in vitro and in vivo applications of betaine were also able to rescue a trafficking-defective FVIII mutant (FVIIIQ305P). We conclude that chemical chaperones such as betaine might represent a useful treatment concept for hemophilia and other diseases caused by deficient intracellular protein trafficking.
format	article
author	Stefanie D Roth Jörg Schüttrumpf Peter Milanov Daniela Abriss Christopher Ungerer Patricia Quade-Lyssy Jeremy C Simpson Rainer Pepperkok Erhard Seifried Torsten Tonn
author_facet	Stefanie D Roth Jörg Schüttrumpf Peter Milanov Daniela Abriss Christopher Ungerer Patricia Quade-Lyssy Jeremy C Simpson Rainer Pepperkok Erhard Seifried Torsten Tonn
author_sort	Stefanie D Roth
title	Chemical chaperones improve protein secretion and rescue mutant factor VIII in mice with hemophilia A.
title_short	Chemical chaperones improve protein secretion and rescue mutant factor VIII in mice with hemophilia A.
title_full	Chemical chaperones improve protein secretion and rescue mutant factor VIII in mice with hemophilia A.
title_fullStr	Chemical chaperones improve protein secretion and rescue mutant factor VIII in mice with hemophilia A.
title_full_unstemmed	Chemical chaperones improve protein secretion and rescue mutant factor VIII in mice with hemophilia A.
title_sort	chemical chaperones improve protein secretion and rescue mutant factor viii in mice with hemophilia a.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/c3ff58452a9c4d699c82179d32d05aaf
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Chemical chaperones improve protein secretion and rescue mutant factor VIII in mice with hemophilia A.

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