XBP1s regulates MUC5B in a promoter variant-dependent pathway in idiopathic pulmonary fibrosis airway epithelia

Gang Chen, Carla M.P. Ribeiro, Ling Sun, Kenichi Okuda, Takafumi Kato, Rodney C. Gilmore, Mary B. Martino, Hong Dang, Aiman Abzhanova, Jennifer M. Lin, Emily A. Hull-Ryde, Allison S. Volmer, Scott H. Randell, Alessandra Livraghi-Butrico, Yingfeng Deng, Philipp E Scherer, Barry R. Stripp, Wanda K. O'Neal, Richard C. Boucher

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Rationale: The goal was to connect elements of idiopathic pulmonary fibrosis (IPF) pathogenesis, including chronic endoplasmic reticulum stress in respiratory epithelia associated with injury/inflammation and remodeling, distal airway mucus obstruction and honeycomb cyst formation with accumulation of MUC5B (mucin 5B), and associations between IPF risk and polymorphisms in the MUC5B promoter. Objectives: To test whether the endoplasmic reticulum (ER) stress sensor protein ERN2 (ER-to-nucleus signaling 2) and its downstream effector, the spliced form of XBP1S (X-box-binding protein 1), regulate MUC5B expression and differentially activate the MUC5B promoter variant in respiratory epithelia. Methods: Primary human airway epithelial (HAE) cells, transgenic mouse models, human IPF lung tissues, and cell lines expressing XBP1S and MUC5B promoters were used to explore relationships between the ERN2/XBP1S pathway and MUC5B. An inhibitor of the pathway, KIRA6, and XBP1 CRISPR-Cas9 were used in HAE cells to explore therapeutic potential. Measurements and Main Results: ERN2 regulated MUC5B and MUC5AC mRNAs. Downstream XBP1S selectively promoted MUC5B expression in vitro and in distal murine airway epithelia in vivo. XBP1S bound to the proximal region of the MUC5B promoter and differentially upregulated MUC5B expression in the context of the MUC5B promoter rs35705950 variant. High levels of ERN2 and XBP1S were associated with excessive MUC5B mRNAs in distal airways of human IPF lungs. Cytokine-induced MUC5B expression in HAE cells was inhibited by KIRA6 and XBP1 CRISPR-Cas9. Conclusions: A positive feedback bistable ERN2-XBP1S pathway regulates MUC5B-dominated mucus obstruction in IPF, providing an unfolded protein response-dependent mechanism linking the MUC5B promoter rs35705950 polymorphism with IPF pathogenesis. Inhibiting ERN2-dependent pathways/elements may provide a therapeutic option for IPF.

Original languageEnglish (US)
Pages (from-to)220-234
Number of pages15
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume200
Issue number2
DOIs
StatePublished - Jan 1 2019

Fingerprint

Mucin-5B
Idiopathic Pulmonary Fibrosis
Epithelium
Clustered Regularly Interspaced Short Palindromic Repeats
Respiratory Mucosa
Endoplasmic Reticulum Stress
Epithelial Cells
Mucus

Keywords

  • Airway epithelia
  • IPF
  • MUC5B

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

XBP1s regulates MUC5B in a promoter variant-dependent pathway in idiopathic pulmonary fibrosis airway epithelia. / Chen, Gang; Ribeiro, Carla M.P.; Sun, Ling; Okuda, Kenichi; Kato, Takafumi; Gilmore, Rodney C.; Martino, Mary B.; Dang, Hong; Abzhanova, Aiman; Lin, Jennifer M.; Hull-Ryde, Emily A.; Volmer, Allison S.; Randell, Scott H.; Livraghi-Butrico, Alessandra; Deng, Yingfeng; Scherer, Philipp E; Stripp, Barry R.; O'Neal, Wanda K.; Boucher, Richard C.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 200, No. 2, 01.01.2019, p. 220-234.

Research output: Contribution to journalArticle

Chen, G, Ribeiro, CMP, Sun, L, Okuda, K, Kato, T, Gilmore, RC, Martino, MB, Dang, H, Abzhanova, A, Lin, JM, Hull-Ryde, EA, Volmer, AS, Randell, SH, Livraghi-Butrico, A, Deng, Y, Scherer, PE, Stripp, BR, O'Neal, WK & Boucher, RC 2019, 'XBP1s regulates MUC5B in a promoter variant-dependent pathway in idiopathic pulmonary fibrosis airway epithelia', American Journal of Respiratory and Critical Care Medicine, vol. 200, no. 2, pp. 220-234. https://doi.org/10.1164/rccm.201810-1972OC
Chen, Gang ; Ribeiro, Carla M.P. ; Sun, Ling ; Okuda, Kenichi ; Kato, Takafumi ; Gilmore, Rodney C. ; Martino, Mary B. ; Dang, Hong ; Abzhanova, Aiman ; Lin, Jennifer M. ; Hull-Ryde, Emily A. ; Volmer, Allison S. ; Randell, Scott H. ; Livraghi-Butrico, Alessandra ; Deng, Yingfeng ; Scherer, Philipp E ; Stripp, Barry R. ; O'Neal, Wanda K. ; Boucher, Richard C. / XBP1s regulates MUC5B in a promoter variant-dependent pathway in idiopathic pulmonary fibrosis airway epithelia. In: American Journal of Respiratory and Critical Care Medicine. 2019 ; Vol. 200, No. 2. pp. 220-234.
@article{2a8576a47f214c6eb02a96200aa20323,
title = "XBP1s regulates MUC5B in a promoter variant-dependent pathway in idiopathic pulmonary fibrosis airway epithelia",
abstract = "Rationale: The goal was to connect elements of idiopathic pulmonary fibrosis (IPF) pathogenesis, including chronic endoplasmic reticulum stress in respiratory epithelia associated with injury/inflammation and remodeling, distal airway mucus obstruction and honeycomb cyst formation with accumulation of MUC5B (mucin 5B), and associations between IPF risk and polymorphisms in the MUC5B promoter. Objectives: To test whether the endoplasmic reticulum (ER) stress sensor protein ERN2 (ER-to-nucleus signaling 2) and its downstream effector, the spliced form of XBP1S (X-box-binding protein 1), regulate MUC5B expression and differentially activate the MUC5B promoter variant in respiratory epithelia. Methods: Primary human airway epithelial (HAE) cells, transgenic mouse models, human IPF lung tissues, and cell lines expressing XBP1S and MUC5B promoters were used to explore relationships between the ERN2/XBP1S pathway and MUC5B. An inhibitor of the pathway, KIRA6, and XBP1 CRISPR-Cas9 were used in HAE cells to explore therapeutic potential. Measurements and Main Results: ERN2 regulated MUC5B and MUC5AC mRNAs. Downstream XBP1S selectively promoted MUC5B expression in vitro and in distal murine airway epithelia in vivo. XBP1S bound to the proximal region of the MUC5B promoter and differentially upregulated MUC5B expression in the context of the MUC5B promoter rs35705950 variant. High levels of ERN2 and XBP1S were associated with excessive MUC5B mRNAs in distal airways of human IPF lungs. Cytokine-induced MUC5B expression in HAE cells was inhibited by KIRA6 and XBP1 CRISPR-Cas9. Conclusions: A positive feedback bistable ERN2-XBP1S pathway regulates MUC5B-dominated mucus obstruction in IPF, providing an unfolded protein response-dependent mechanism linking the MUC5B promoter rs35705950 polymorphism with IPF pathogenesis. Inhibiting ERN2-dependent pathways/elements may provide a therapeutic option for IPF.",
keywords = "Airway epithelia, IPF, MUC5B",
author = "Gang Chen and Ribeiro, {Carla M.P.} and Ling Sun and Kenichi Okuda and Takafumi Kato and Gilmore, {Rodney C.} and Martino, {Mary B.} and Hong Dang and Aiman Abzhanova and Lin, {Jennifer M.} and Hull-Ryde, {Emily A.} and Volmer, {Allison S.} and Randell, {Scott H.} and Alessandra Livraghi-Butrico and Yingfeng Deng and Scherer, {Philipp E} and Stripp, {Barry R.} and O'Neal, {Wanda K.} and Boucher, {Richard C.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1164/rccm.201810-1972OC",
language = "English (US)",
volume = "200",
pages = "220--234",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "2",

}

TY - JOUR

T1 - XBP1s regulates MUC5B in a promoter variant-dependent pathway in idiopathic pulmonary fibrosis airway epithelia

AU - Chen, Gang

AU - Ribeiro, Carla M.P.

AU - Sun, Ling

AU - Okuda, Kenichi

AU - Kato, Takafumi

AU - Gilmore, Rodney C.

AU - Martino, Mary B.

AU - Dang, Hong

AU - Abzhanova, Aiman

AU - Lin, Jennifer M.

AU - Hull-Ryde, Emily A.

AU - Volmer, Allison S.

AU - Randell, Scott H.

AU - Livraghi-Butrico, Alessandra

AU - Deng, Yingfeng

AU - Scherer, Philipp E

AU - Stripp, Barry R.

AU - O'Neal, Wanda K.

AU - Boucher, Richard C.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Rationale: The goal was to connect elements of idiopathic pulmonary fibrosis (IPF) pathogenesis, including chronic endoplasmic reticulum stress in respiratory epithelia associated with injury/inflammation and remodeling, distal airway mucus obstruction and honeycomb cyst formation with accumulation of MUC5B (mucin 5B), and associations between IPF risk and polymorphisms in the MUC5B promoter. Objectives: To test whether the endoplasmic reticulum (ER) stress sensor protein ERN2 (ER-to-nucleus signaling 2) and its downstream effector, the spliced form of XBP1S (X-box-binding protein 1), regulate MUC5B expression and differentially activate the MUC5B promoter variant in respiratory epithelia. Methods: Primary human airway epithelial (HAE) cells, transgenic mouse models, human IPF lung tissues, and cell lines expressing XBP1S and MUC5B promoters were used to explore relationships between the ERN2/XBP1S pathway and MUC5B. An inhibitor of the pathway, KIRA6, and XBP1 CRISPR-Cas9 were used in HAE cells to explore therapeutic potential. Measurements and Main Results: ERN2 regulated MUC5B and MUC5AC mRNAs. Downstream XBP1S selectively promoted MUC5B expression in vitro and in distal murine airway epithelia in vivo. XBP1S bound to the proximal region of the MUC5B promoter and differentially upregulated MUC5B expression in the context of the MUC5B promoter rs35705950 variant. High levels of ERN2 and XBP1S were associated with excessive MUC5B mRNAs in distal airways of human IPF lungs. Cytokine-induced MUC5B expression in HAE cells was inhibited by KIRA6 and XBP1 CRISPR-Cas9. Conclusions: A positive feedback bistable ERN2-XBP1S pathway regulates MUC5B-dominated mucus obstruction in IPF, providing an unfolded protein response-dependent mechanism linking the MUC5B promoter rs35705950 polymorphism with IPF pathogenesis. Inhibiting ERN2-dependent pathways/elements may provide a therapeutic option for IPF.

AB - Rationale: The goal was to connect elements of idiopathic pulmonary fibrosis (IPF) pathogenesis, including chronic endoplasmic reticulum stress in respiratory epithelia associated with injury/inflammation and remodeling, distal airway mucus obstruction and honeycomb cyst formation with accumulation of MUC5B (mucin 5B), and associations between IPF risk and polymorphisms in the MUC5B promoter. Objectives: To test whether the endoplasmic reticulum (ER) stress sensor protein ERN2 (ER-to-nucleus signaling 2) and its downstream effector, the spliced form of XBP1S (X-box-binding protein 1), regulate MUC5B expression and differentially activate the MUC5B promoter variant in respiratory epithelia. Methods: Primary human airway epithelial (HAE) cells, transgenic mouse models, human IPF lung tissues, and cell lines expressing XBP1S and MUC5B promoters were used to explore relationships between the ERN2/XBP1S pathway and MUC5B. An inhibitor of the pathway, KIRA6, and XBP1 CRISPR-Cas9 were used in HAE cells to explore therapeutic potential. Measurements and Main Results: ERN2 regulated MUC5B and MUC5AC mRNAs. Downstream XBP1S selectively promoted MUC5B expression in vitro and in distal murine airway epithelia in vivo. XBP1S bound to the proximal region of the MUC5B promoter and differentially upregulated MUC5B expression in the context of the MUC5B promoter rs35705950 variant. High levels of ERN2 and XBP1S were associated with excessive MUC5B mRNAs in distal airways of human IPF lungs. Cytokine-induced MUC5B expression in HAE cells was inhibited by KIRA6 and XBP1 CRISPR-Cas9. Conclusions: A positive feedback bistable ERN2-XBP1S pathway regulates MUC5B-dominated mucus obstruction in IPF, providing an unfolded protein response-dependent mechanism linking the MUC5B promoter rs35705950 polymorphism with IPF pathogenesis. Inhibiting ERN2-dependent pathways/elements may provide a therapeutic option for IPF.

KW - Airway epithelia

KW - IPF

KW - MUC5B

UR - http://www.scopus.com/inward/record.url?scp=85068824175&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068824175&partnerID=8YFLogxK

U2 - 10.1164/rccm.201810-1972OC

DO - 10.1164/rccm.201810-1972OC

M3 - Article

C2 - 30973754

AN - SCOPUS:85068824175

VL - 200

SP - 220

EP - 234

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 2

ER -