Endoplasmic reticulum stress regulates the innate immunity critical transcription factor IRF3

Yi Ping Liu, Ling Zeng, Austin T. Tian, Ashley Bomkamp, Daniel Rivera, Delia Gutman, Glen N Barber, Julie K. Olson, Judith A. Smith

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

IFN regulatory factor 3 (IRF3) regulates early type I IFNs and other genes involved in innate immunity. We have previously shown that cells undergoing an endoplasmic reticulum (ER) stress response called the unfolded protein response produce synergistically augmented IFN-β when stimulated with pattern recognition receptor agonists such as LPS. Concomitant ER stress and LPS stimulation resulted in greater recruitment of the IRF3 transcription factor to ifnb1 gene regulatory elements. In this study, we used murine cells to demonstrate that both oxygen-glucose deprivation and pharmacologic unfolded protein response inducers trigger phosphorylation and nuclear translocation of IRF3, even in the absence of exogenous LPS. Different ER stressors used distinct mechanisms to activate IRF3: IRF3 phosphorylation due to calcium-mobilizing ER stress (thapsigargin treatment, oxygen-glucose deprivation) critically depended upon stimulator of IFN gene, an ER-resident nucleic acid-responsive molecule. However, calcium mobilization alone by ionomycin was insufficient for IRF3 phosphorylation. In contrast, other forms of ER stress (e.g., tunicamycin treatment) promote IRF3 phosphorylation independently of stimulator of IFN gene and TANK-binding kinase 1. Rather, IRF3 activation by tunicamycin and 2-deoxyglucose was inhibited by 4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride, a serine protease inhibitor that blocks activating transcription factor 6 processing. Interfering with ER stress-induced IRF3 activation abrogated IFN-β synergy. Together, these data suggest ER stress primes cells to respond to innate immune stimuli by activating the IRF3 transcription factor. Our results also suggest certain types of ER stress accomplish IRF3 phosphorylation by co-opting existing innate immune pathogen response pathways. These data have implications for diseases involving ER stress and type I IFN.

Original languageEnglish
Pages (from-to)4630-4639
Number of pages10
JournalJournal of Immunology
Volume189
Issue number9
DOIs
StatePublished - Nov 1 2012

Fingerprint

Interferon Regulatory Factor-3
Endoplasmic Reticulum Stress
Innate Immunity
Transcription Factors
Phosphorylation
Unfolded Protein Response
Tunicamycin
Endoplasmic Reticulum
Activating Transcription Factor 6
Oxygen
Genes
Calcium
Pattern Recognition Receptors
Glucose
Ionomycin
Serine Proteinase Inhibitors
Thapsigargin
Deoxyglucose
Regulator Genes
Nucleic Acids

ASJC Scopus subject areas

  • Immunology

Cite this

Liu, Y. P., Zeng, L., Tian, A. T., Bomkamp, A., Rivera, D., Gutman, D., ... Smith, J. A. (2012). Endoplasmic reticulum stress regulates the innate immunity critical transcription factor IRF3. Journal of Immunology, 189(9), 4630-4639. https://doi.org/10.4049/jimmunol.1102737

Endoplasmic reticulum stress regulates the innate immunity critical transcription factor IRF3. / Liu, Yi Ping; Zeng, Ling; Tian, Austin T.; Bomkamp, Ashley; Rivera, Daniel; Gutman, Delia; Barber, Glen N; Olson, Julie K.; Smith, Judith A.

In: Journal of Immunology, Vol. 189, No. 9, 01.11.2012, p. 4630-4639.

Research output: Contribution to journalArticle

Liu, YP, Zeng, L, Tian, AT, Bomkamp, A, Rivera, D, Gutman, D, Barber, GN, Olson, JK & Smith, JA 2012, 'Endoplasmic reticulum stress regulates the innate immunity critical transcription factor IRF3', Journal of Immunology, vol. 189, no. 9, pp. 4630-4639. https://doi.org/10.4049/jimmunol.1102737
Liu, Yi Ping ; Zeng, Ling ; Tian, Austin T. ; Bomkamp, Ashley ; Rivera, Daniel ; Gutman, Delia ; Barber, Glen N ; Olson, Julie K. ; Smith, Judith A. / Endoplasmic reticulum stress regulates the innate immunity critical transcription factor IRF3. In: Journal of Immunology. 2012 ; Vol. 189, No. 9. pp. 4630-4639.
@article{4a5046ed6b184ce78810791825701d08,
title = "Endoplasmic reticulum stress regulates the innate immunity critical transcription factor IRF3",
abstract = "IFN regulatory factor 3 (IRF3) regulates early type I IFNs and other genes involved in innate immunity. We have previously shown that cells undergoing an endoplasmic reticulum (ER) stress response called the unfolded protein response produce synergistically augmented IFN-β when stimulated with pattern recognition receptor agonists such as LPS. Concomitant ER stress and LPS stimulation resulted in greater recruitment of the IRF3 transcription factor to ifnb1 gene regulatory elements. In this study, we used murine cells to demonstrate that both oxygen-glucose deprivation and pharmacologic unfolded protein response inducers trigger phosphorylation and nuclear translocation of IRF3, even in the absence of exogenous LPS. Different ER stressors used distinct mechanisms to activate IRF3: IRF3 phosphorylation due to calcium-mobilizing ER stress (thapsigargin treatment, oxygen-glucose deprivation) critically depended upon stimulator of IFN gene, an ER-resident nucleic acid-responsive molecule. However, calcium mobilization alone by ionomycin was insufficient for IRF3 phosphorylation. In contrast, other forms of ER stress (e.g., tunicamycin treatment) promote IRF3 phosphorylation independently of stimulator of IFN gene and TANK-binding kinase 1. Rather, IRF3 activation by tunicamycin and 2-deoxyglucose was inhibited by 4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride, a serine protease inhibitor that blocks activating transcription factor 6 processing. Interfering with ER stress-induced IRF3 activation abrogated IFN-β synergy. Together, these data suggest ER stress primes cells to respond to innate immune stimuli by activating the IRF3 transcription factor. Our results also suggest certain types of ER stress accomplish IRF3 phosphorylation by co-opting existing innate immune pathogen response pathways. These data have implications for diseases involving ER stress and type I IFN.",
author = "Liu, {Yi Ping} and Ling Zeng and Tian, {Austin T.} and Ashley Bomkamp and Daniel Rivera and Delia Gutman and Barber, {Glen N} and Olson, {Julie K.} and Smith, {Judith A.}",
year = "2012",
month = "11",
day = "1",
doi = "10.4049/jimmunol.1102737",
language = "English",
volume = "189",
pages = "4630--4639",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "9",

}

TY - JOUR

T1 - Endoplasmic reticulum stress regulates the innate immunity critical transcription factor IRF3

AU - Liu, Yi Ping

AU - Zeng, Ling

AU - Tian, Austin T.

AU - Bomkamp, Ashley

AU - Rivera, Daniel

AU - Gutman, Delia

AU - Barber, Glen N

AU - Olson, Julie K.

AU - Smith, Judith A.

PY - 2012/11/1

Y1 - 2012/11/1

N2 - IFN regulatory factor 3 (IRF3) regulates early type I IFNs and other genes involved in innate immunity. We have previously shown that cells undergoing an endoplasmic reticulum (ER) stress response called the unfolded protein response produce synergistically augmented IFN-β when stimulated with pattern recognition receptor agonists such as LPS. Concomitant ER stress and LPS stimulation resulted in greater recruitment of the IRF3 transcription factor to ifnb1 gene regulatory elements. In this study, we used murine cells to demonstrate that both oxygen-glucose deprivation and pharmacologic unfolded protein response inducers trigger phosphorylation and nuclear translocation of IRF3, even in the absence of exogenous LPS. Different ER stressors used distinct mechanisms to activate IRF3: IRF3 phosphorylation due to calcium-mobilizing ER stress (thapsigargin treatment, oxygen-glucose deprivation) critically depended upon stimulator of IFN gene, an ER-resident nucleic acid-responsive molecule. However, calcium mobilization alone by ionomycin was insufficient for IRF3 phosphorylation. In contrast, other forms of ER stress (e.g., tunicamycin treatment) promote IRF3 phosphorylation independently of stimulator of IFN gene and TANK-binding kinase 1. Rather, IRF3 activation by tunicamycin and 2-deoxyglucose was inhibited by 4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride, a serine protease inhibitor that blocks activating transcription factor 6 processing. Interfering with ER stress-induced IRF3 activation abrogated IFN-β synergy. Together, these data suggest ER stress primes cells to respond to innate immune stimuli by activating the IRF3 transcription factor. Our results also suggest certain types of ER stress accomplish IRF3 phosphorylation by co-opting existing innate immune pathogen response pathways. These data have implications for diseases involving ER stress and type I IFN.

AB - IFN regulatory factor 3 (IRF3) regulates early type I IFNs and other genes involved in innate immunity. We have previously shown that cells undergoing an endoplasmic reticulum (ER) stress response called the unfolded protein response produce synergistically augmented IFN-β when stimulated with pattern recognition receptor agonists such as LPS. Concomitant ER stress and LPS stimulation resulted in greater recruitment of the IRF3 transcription factor to ifnb1 gene regulatory elements. In this study, we used murine cells to demonstrate that both oxygen-glucose deprivation and pharmacologic unfolded protein response inducers trigger phosphorylation and nuclear translocation of IRF3, even in the absence of exogenous LPS. Different ER stressors used distinct mechanisms to activate IRF3: IRF3 phosphorylation due to calcium-mobilizing ER stress (thapsigargin treatment, oxygen-glucose deprivation) critically depended upon stimulator of IFN gene, an ER-resident nucleic acid-responsive molecule. However, calcium mobilization alone by ionomycin was insufficient for IRF3 phosphorylation. In contrast, other forms of ER stress (e.g., tunicamycin treatment) promote IRF3 phosphorylation independently of stimulator of IFN gene and TANK-binding kinase 1. Rather, IRF3 activation by tunicamycin and 2-deoxyglucose was inhibited by 4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride, a serine protease inhibitor that blocks activating transcription factor 6 processing. Interfering with ER stress-induced IRF3 activation abrogated IFN-β synergy. Together, these data suggest ER stress primes cells to respond to innate immune stimuli by activating the IRF3 transcription factor. Our results also suggest certain types of ER stress accomplish IRF3 phosphorylation by co-opting existing innate immune pathogen response pathways. These data have implications for diseases involving ER stress and type I IFN.

UR - http://www.scopus.com/inward/record.url?scp=84867911096&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867911096&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1102737

DO - 10.4049/jimmunol.1102737

M3 - Article

C2 - 23028052

AN - SCOPUS:84867911096

VL - 189

SP - 4630

EP - 4639

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 9

ER -