NRF2-dependent gene expression promotes ciliogenesis and Hedgehog signaling
Entity
UAM. Departamento de BioquímicaPublisher
Nature Research (part of Springer Nature)Date
2019-09-25Citation
10.1038/s41598-019-50356-0
Scientific Reports 9 (2019): 13896
ISSN
2045-2322DOI
10.1038/s41598-019-50356-0Funded by
This work was supported by European Regional Development Fund (ERDF)-cofunded grants from the Spanish Ministry of Economy and Competitiveness (MINECO) to FRGG (SAF2015-66568-R and RYC2013-14887) and to A.C. and I.L.B. (SAF2016-76520-R)Project
Gobierno de España. SAF2015-66568-R; Gobierno de España. RYC2013-14887; Gobierno de España. SAF2016-76520-REditor's Version
https://doi.org/10.1038/s41598-019-50356-0Subjects
Reagents, plasmids and antibodies; Cell culture; Hedgehog signaling; NRF2; Biología y Biomedicina / BiologíaRights
© The Author(s) 2019Abstract
The transcription factor NRF2 is a master regulator of cellular antioxidant and detoxification responses, but it also regulates other processes such as autophagy and pluripotency. In human embryonic stem cells (hESCs), NRF2 antagonizes neuroectoderm differentiation, which only occurs after NRF2 is repressed via a Primary Cilia-Autophagy-NRF2 (PAN) axis. However, the functional connections between NRF2 and primary cilia, microtubule-based plasma membrane protrusions that function as cellular antennae, remain poorly understood. For instance, nothing is known about whether NRF2 affects cilia, or whether cilia regulation of NRF2 extends beyond hESCs. Here, we show that NRF2 and primary cilia reciprocally regulate each other. First, we demonstrate that fibroblasts lacking primary cilia have higher NRF2 activity, which is rescued by autophagy-activating mTOR inhibitors, indicating that the PAN axis also operates in differentiated cells. Furthermore, NRF2 controls cilia formation and function. NRF2-null cells grow fewer and shorter cilia and display impaired Hedgehog signaling, a cilia-dependent pathway. These defects are not due to increased oxidative stress or ciliophagy, but rather to NRF2 promoting expression of multiple ciliogenic and Hedgehog pathway genes. Among these, we focused on GLI2 and GLI3, the transcription factors controlling Hh pathway output. Both their mRNA and protein levels are reduced in NRF2-null cells, consistent with their gene promoters containing consensus ARE sequences predicted to bind NRF2. Moreover, GLI2 and GLI3 fail to accumulate at the ciliary tip of NRF2-null cells upon Hh pathway activation. Given the importance of NRF2 and ciliary signaling in human disease, our data may have important biomedical implications
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Google Scholar:Martín-Hurtado, Ana
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Martin-Morales, Raquel
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Robledinos-Antón, Natalia
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Blanco, Ruth
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Palacios-Blanco, Inés
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Lastres Becker, Isabel
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Cuadrado Pastor, Antonio
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García-Gonzalo, Francesc R.
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