NRF2-dependent gene expression promotes ciliogenesis and Hedgehog signaling
Identifieur interne : 000604 ( Main/Merge ); précédent : 000603; suivant : 000605NRF2-dependent gene expression promotes ciliogenesis and Hedgehog signaling
Auteurs : Ana Martin-Hurtado [Espagne] ; Raquel Martin-Morales [Espagne] ; Natalia Robledinos-Ant N [Espagne] ; Ruth Blanco [Espagne] ; Ines Palacios-Blanco [Espagne] ; Isabel Lastres-Becker [Espagne] ; Antonio Cuadrado [Espagne] ; Francesc R. Garcia-Gonzalo [Espagne]Source :
- Scientific Reports [ 2045-2322 ] ; 2019.
Abstract
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.
Url:
DOI: 10.1038/s41598-019-50356-0
PubMed: 31554934
PubMed Central: 6761261
Links toward previous steps (curation, corpus...)
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PMC:6761261Le document en format XML
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<institution>Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII,</institution>
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Madrid, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Madrid</wicri:regionArea>
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</author>
<author><name sortKey="Cuadrado, Antonio" sort="Cuadrado, Antonio" uniqKey="Cuadrado A" first="Antonio" last="Cuadrado">Antonio Cuadrado</name>
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<institution>Alberto Sols Biomedical Research Institute UAM-CSIC and Department of Biochemistry, School of Medicine,</institution>
<institution>Autonomous University of Madrid (UAM),</institution>
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Madrid, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Madrid</wicri:regionArea>
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<institution-id institution-id-type="GRID">grid.81821.32</institution-id>
<institution>La Paz University Hospital Research Institute (IdiPAZ),</institution>
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Madrid, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Madrid</wicri:regionArea>
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<institution-id institution-id-type="GRID">grid.413448.e</institution-id>
<institution>Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII,</institution>
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Madrid, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Madrid</wicri:regionArea>
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</author>
<author><name sortKey="Garcia Gonzalo, Francesc R" sort="Garcia Gonzalo, Francesc R" uniqKey="Garcia Gonzalo F" first="Francesc R." last="Garcia-Gonzalo">Francesc R. Garcia-Gonzalo</name>
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<institution-id institution-id-type="GRID">grid.5515.4</institution-id>
<institution>Alberto Sols Biomedical Research Institute UAM-CSIC and Department of Biochemistry, School of Medicine,</institution>
<institution>Autonomous University of Madrid (UAM),</institution>
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Madrid, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Madrid</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8970 9163</institution-id>
<institution-id institution-id-type="GRID">grid.81821.32</institution-id>
<institution>La Paz University Hospital Research Institute (IdiPAZ),</institution>
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Madrid, Spain</nlm:aff>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Madrid</wicri:regionArea>
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</analytic>
<series><title level="j">Scientific Reports</title>
<idno type="eISSN">2045-2322</idno>
<imprint><date when="2019">2019</date>
</imprint>
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<front><div type="abstract" xml:lang="en"><p id="Par1">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.</p>
</div>
</front>
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<author><name sortKey="Garcia Verdugo, Jm" uniqKey="Garcia Verdugo J">JM Garcia-Verdugo</name>
</author>
<author><name sortKey="Reiter, Jf" uniqKey="Reiter J">JF Reiter</name>
</author>
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