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

Raquel M. Melero-Fernandez de Mera, Li-Li Li, Arkadiusz Popinigis, Katryna Cisek, Minna Tuittila, Leena Yadav, Andrius Serva and Michael J. Courtney ()
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Raquel M. Melero-Fernandez de Mera: Molecular Signalling Laboratory, A.I. Virtanen Institute, University of Eastern Finland
Li-Li Li: Molecular Signalling Laboratory, A.I. Virtanen Institute, University of Eastern Finland
Arkadiusz Popinigis: Neuronal Signalling Laboratory, Turku Centre for Biotechnology, University of Turku and Åbo Akademi University
Katryna Cisek: Molecular Signalling Laboratory, A.I. Virtanen Institute, University of Eastern Finland
Minna Tuittila: Neuronal Signalling Laboratory, Turku Centre for Biotechnology, University of Turku and Åbo Akademi University
Leena Yadav: Molecular Signalling Laboratory, A.I. Virtanen Institute, University of Eastern Finland
Andrius Serva: Molecular Signalling Laboratory, A.I. Virtanen Institute, University of Eastern Finland
Michael J. Courtney: Molecular Signalling Laboratory, A.I. Virtanen Institute, University of Eastern Finland

Nature Communications, 2017, vol. 8, issue 1, 1-18

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms15017

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