Targeting DNAJB9, a novel ER luminal co-chaperone, to rescue ΔF508-CFTR

Abstract The molecular mechanism of Endoplasmic Reticulum-associated degradation (ERAD) of Cystic fibrosis transmembrane-conductance regulator (CFTR) is largely unknown. Particularly, it is unknown what ER luminal factor(s) are involved in ERAD. Herein, we used ProtoArray to identify an ER luminal c...

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Autores principales:	Yunjie Huang, Kavisha Arora, Kyu Shik Mun, Fanmuyi Yang, ChangSuk Moon, Sunitha Yarlagadda, Anil Jegga, Timothy Weaver, Anjaparavanda P. Naren
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a9ead2c7e3d246a98726846c361c73db
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spelling	oai:doaj.org-article:a9ead2c7e3d246a98726846c361c73db2021-12-02T15:08:21ZTargeting DNAJB9, a novel ER luminal co-chaperone, to rescue ΔF508-CFTR10.1038/s41598-019-46161-42045-2322https://doaj.org/article/a9ead2c7e3d246a98726846c361c73db2019-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-46161-4https://doaj.org/toc/2045-2322Abstract The molecular mechanism of Endoplasmic Reticulum-associated degradation (ERAD) of Cystic fibrosis transmembrane-conductance regulator (CFTR) is largely unknown. Particularly, it is unknown what ER luminal factor(s) are involved in ERAD. Herein, we used ProtoArray to identify an ER luminal co-chaperone, DNAJB9, which can directly interact with CFTR. For both WT- and ΔF508 (deletion of phenylalanine at position 508, the most common CF-causing mutant)-CFTR, knockdown of DNAJB9 by siRNA increased their expression levels on the cell surface and, consequently, upregulated their function. Furthermore, genetic ablation of DNAJB9 in WT mice increased CFTR expression and enhanced CFTR-dependent fluid secretion in enteroids. Importantly, DNAJB9 deficiency upregulated enteroids’ fluid secretion in CF mice (homozygous for ΔF508), and silencing one allele of DNAJB9 is sufficient to rescue ΔF508-CFTR in vitro and in vivo, suggesting that DNAJB9 may be a rate-limiting factor in CFTR ERAD pathway. Our studies identified the first ER luminal co-chaperone involved in CFTR ERAD, and DNAJB9 could be a novel therapeutic target for CF.Yunjie HuangKavisha AroraKyu Shik MunFanmuyi YangChangSuk MoonSunitha YarlagaddaAnil JeggaTimothy WeaverAnjaparavanda P. NarenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-11 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yunjie Huang Kavisha Arora Kyu Shik Mun Fanmuyi Yang ChangSuk Moon Sunitha Yarlagadda Anil Jegga Timothy Weaver Anjaparavanda P. Naren Targeting DNAJB9, a novel ER luminal co-chaperone, to rescue ΔF508-CFTR
description	Abstract The molecular mechanism of Endoplasmic Reticulum-associated degradation (ERAD) of Cystic fibrosis transmembrane-conductance regulator (CFTR) is largely unknown. Particularly, it is unknown what ER luminal factor(s) are involved in ERAD. Herein, we used ProtoArray to identify an ER luminal co-chaperone, DNAJB9, which can directly interact with CFTR. For both WT- and ΔF508 (deletion of phenylalanine at position 508, the most common CF-causing mutant)-CFTR, knockdown of DNAJB9 by siRNA increased their expression levels on the cell surface and, consequently, upregulated their function. Furthermore, genetic ablation of DNAJB9 in WT mice increased CFTR expression and enhanced CFTR-dependent fluid secretion in enteroids. Importantly, DNAJB9 deficiency upregulated enteroids’ fluid secretion in CF mice (homozygous for ΔF508), and silencing one allele of DNAJB9 is sufficient to rescue ΔF508-CFTR in vitro and in vivo, suggesting that DNAJB9 may be a rate-limiting factor in CFTR ERAD pathway. Our studies identified the first ER luminal co-chaperone involved in CFTR ERAD, and DNAJB9 could be a novel therapeutic target for CF.
format	article
author	Yunjie Huang Kavisha Arora Kyu Shik Mun Fanmuyi Yang ChangSuk Moon Sunitha Yarlagadda Anil Jegga Timothy Weaver Anjaparavanda P. Naren
author_facet	Yunjie Huang Kavisha Arora Kyu Shik Mun Fanmuyi Yang ChangSuk Moon Sunitha Yarlagadda Anil Jegga Timothy Weaver Anjaparavanda P. Naren
author_sort	Yunjie Huang
title	Targeting DNAJB9, a novel ER luminal co-chaperone, to rescue ΔF508-CFTR
title_short	Targeting DNAJB9, a novel ER luminal co-chaperone, to rescue ΔF508-CFTR
title_full	Targeting DNAJB9, a novel ER luminal co-chaperone, to rescue ΔF508-CFTR
title_fullStr	Targeting DNAJB9, a novel ER luminal co-chaperone, to rescue ΔF508-CFTR
title_full_unstemmed	Targeting DNAJB9, a novel ER luminal co-chaperone, to rescue ΔF508-CFTR
title_sort	targeting dnajb9, a novel er luminal co-chaperone, to rescue δf508-cftr
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/a9ead2c7e3d246a98726846c361c73db
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Targeting DNAJB9, a novel ER luminal co-chaperone, to rescue ΔF508-CFTR

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