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A simple optogenetic MAPK inhibitor design reveals resonance between transcription-regulating circuitry and temporally-encoded inputs

Engineering light-sensitive protein regulators has been a tremendous multidisciplinary challenge. Optogenetic regulators of MAPKs, central nodes of cellular regulation, have not previously been described. Here we present OptoJNKi, a light-regulated JNK inhibitor based on the AsLOV2 light-sensor doma...

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Autores principales: Melero-Fernandez de Mera, Raquel M., Li, Li-Li, Popinigis, Arkadiusz, Cisek, Katryna, Tuittila, Minna, Yadav, Leena, Serva, Andrius, Courtney, Michael J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437309/
https://www.ncbi.nlm.nih.gov/pubmed/28497795
http://dx.doi.org/10.1038/ncomms15017
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author Melero-Fernandez de Mera, Raquel M.
Li, Li-Li
Popinigis, Arkadiusz
Cisek, Katryna
Tuittila, Minna
Yadav, Leena
Serva, Andrius
Courtney, Michael J.
author_facet Melero-Fernandez de Mera, Raquel M.
Li, Li-Li
Popinigis, Arkadiusz
Cisek, Katryna
Tuittila, Minna
Yadav, Leena
Serva, Andrius
Courtney, Michael J.
author_sort Melero-Fernandez de Mera, Raquel M.
collection PubMed
description Engineering light-sensitive protein regulators has been a tremendous multidisciplinary challenge. Optogenetic regulators of MAPKs, central nodes of cellular regulation, have not previously been described. Here we present OptoJNKi, a light-regulated JNK inhibitor based on the AsLOV2 light-sensor domain using the ubiquitous FMN chromophore. OptoJNKi gene-transfer allows optogenetic applications, whereas protein delivery allows optopharmacology. Development of OptoJNKi suggests a design principle for other optically regulated inhibitors. From this, we generate Optop38i, which inhibits p38MAPK in intact illuminated cells. Neurons are known for interpreting temporally-encoded inputs via interplay between ion channels, membrane potential and intracellular calcium. However, the consequences of temporal variation of JNK-regulating trophic inputs, potentially resulting from synaptic activity and reversible cellular protrusions, on downstream targets are unknown. Using OptoJNKi, we reveal maximal regulation of c-Jun transactivation can occur at unexpectedly slow periodicities of inhibition depending on the inhibitor's subcellular location. This provides evidence for resonance in metazoan JNK-signalling circuits.
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spelling pubmed-54373092017-06-01 A simple optogenetic MAPK inhibitor design reveals resonance between transcription-regulating circuitry and temporally-encoded inputs Melero-Fernandez de Mera, Raquel M. Li, Li-Li Popinigis, Arkadiusz Cisek, Katryna Tuittila, Minna Yadav, Leena Serva, Andrius Courtney, Michael J. Nat Commun Article Engineering light-sensitive protein regulators has been a tremendous multidisciplinary challenge. Optogenetic regulators of MAPKs, central nodes of cellular regulation, have not previously been described. Here we present OptoJNKi, a light-regulated JNK inhibitor based on the AsLOV2 light-sensor domain using the ubiquitous FMN chromophore. OptoJNKi gene-transfer allows optogenetic applications, whereas protein delivery allows optopharmacology. Development of OptoJNKi suggests a design principle for other optically regulated inhibitors. From this, we generate Optop38i, which inhibits p38MAPK in intact illuminated cells. Neurons are known for interpreting temporally-encoded inputs via interplay between ion channels, membrane potential and intracellular calcium. However, the consequences of temporal variation of JNK-regulating trophic inputs, potentially resulting from synaptic activity and reversible cellular protrusions, on downstream targets are unknown. Using OptoJNKi, we reveal maximal regulation of c-Jun transactivation can occur at unexpectedly slow periodicities of inhibition depending on the inhibitor's subcellular location. This provides evidence for resonance in metazoan JNK-signalling circuits. Nature Publishing Group 2017-05-12 /pmc/articles/PMC5437309/ /pubmed/28497795 http://dx.doi.org/10.1038/ncomms15017 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Melero-Fernandez de Mera, Raquel M.
Li, Li-Li
Popinigis, Arkadiusz
Cisek, Katryna
Tuittila, Minna
Yadav, Leena
Serva, Andrius
Courtney, Michael J.
A simple optogenetic MAPK inhibitor design reveals resonance between transcription-regulating circuitry and temporally-encoded inputs
title A simple optogenetic MAPK inhibitor design reveals resonance between transcription-regulating circuitry and temporally-encoded inputs
title_full A simple optogenetic MAPK inhibitor design reveals resonance between transcription-regulating circuitry and temporally-encoded inputs
title_fullStr A simple optogenetic MAPK inhibitor design reveals resonance between transcription-regulating circuitry and temporally-encoded inputs
title_full_unstemmed A simple optogenetic MAPK inhibitor design reveals resonance between transcription-regulating circuitry and temporally-encoded inputs
title_short A simple optogenetic MAPK inhibitor design reveals resonance between transcription-regulating circuitry and temporally-encoded inputs
title_sort simple optogenetic mapk inhibitor design reveals resonance between transcription-regulating circuitry and temporally-encoded inputs
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437309/
https://www.ncbi.nlm.nih.gov/pubmed/28497795
http://dx.doi.org/10.1038/ncomms15017
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