TY - JOUR
T1 - RPA1 binding to NRF2 switches ARE-dependent transcriptional activation to ARE-NRE-dependent repression
AU - Liu, Pengfei
AU - De La Vega, Montserrat Rojo
AU - Sammani, Saad
AU - Mascarenhas, Joseph B.
AU - Kerins, Michael
AU - Dodson, Matthew
AU - Sun, Xiaoguang
AU - Wang, Ting
AU - Ooi, Aikseng
AU - Garcia, Joe G.N.
AU - Zhang, Donna D.
N1 - Funding Information:
ACKNOWLEDGMENTS. This work was supported by National Institutes of Health Grants R01 ES026845, R01 DK109555, and P42 ES004940 (to D.D.Z.) and R01 HL91889, P01 HL126609, R01 HL125615, and P01 HL134610 (to J.G.N.G.).
Publisher Copyright:
© 2018 National Academy of Sciences. All rights reserved.
PY - 2018/10/30
Y1 - 2018/10/30
N2 - NRF2 regulates cellular redox homeostasis, metabolic balance, and proteostasis by forming a dimer with small musculoaponeurotic fibrosarcoma proteins (sMAFs) and binding to antioxidant response elements (AREs) to activate target gene transcription. In contrast, NRF2-ARE-dependent transcriptional repression is unreported. Here, we describe NRF2-mediated gene repression via a specific seven-nucleotide sequence flanking the ARE, which we term the NRF2-replication protein A1 (RPA1) element (NRE). Mechanistically, RPA1 competes with sMAF for NRF2 binding, followed by interaction of NRF2-RPA1 with the ARE-NRE and eduction of promoter activity. Genome-wide in silico and RNA-seq analyses revealed this NRF2-RPA1-ARE-NRE complex mediates negative regulation of many genes with diverse functions, indicating that this mechanism is a fundamental cellular process. Notably, repression of MYLK, which encodes the nonmuscle myosin light chain kinase, by the NRF2-RPA1-ARE-NRE complex disrupts vascular integrity in preclinical inflammatory lung injury models, illustrating the translational significance of NRF2-mediated transcriptional repression. Our findings reveal a gene-suppressive function of NRF2 and a subset of negatively regulated NRF2 target genes, underscoring the broad impact of NRF2 in physiological and pathological settings.
AB - NRF2 regulates cellular redox homeostasis, metabolic balance, and proteostasis by forming a dimer with small musculoaponeurotic fibrosarcoma proteins (sMAFs) and binding to antioxidant response elements (AREs) to activate target gene transcription. In contrast, NRF2-ARE-dependent transcriptional repression is unreported. Here, we describe NRF2-mediated gene repression via a specific seven-nucleotide sequence flanking the ARE, which we term the NRF2-replication protein A1 (RPA1) element (NRE). Mechanistically, RPA1 competes with sMAF for NRF2 binding, followed by interaction of NRF2-RPA1 with the ARE-NRE and eduction of promoter activity. Genome-wide in silico and RNA-seq analyses revealed this NRF2-RPA1-ARE-NRE complex mediates negative regulation of many genes with diverse functions, indicating that this mechanism is a fundamental cellular process. Notably, repression of MYLK, which encodes the nonmuscle myosin light chain kinase, by the NRF2-RPA1-ARE-NRE complex disrupts vascular integrity in preclinical inflammatory lung injury models, illustrating the translational significance of NRF2-mediated transcriptional repression. Our findings reveal a gene-suppressive function of NRF2 and a subset of negatively regulated NRF2 target genes, underscoring the broad impact of NRF2 in physiological and pathological settings.
KW - Acute lung injury
KW - MYLK/MLCK
KW - NRF2
KW - RPA1
KW - Transcriptional regulation
UR - http://www.scopus.com/inward/record.url?scp=85055670050&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055670050&partnerID=8YFLogxK
U2 - 10.1073/pnas.1812125115
DO - 10.1073/pnas.1812125115
M3 - Article
C2 - 30309964
AN - SCOPUS:85055670050
VL - 115
SP - E10352-E10361
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 44
ER -