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

Nature Communications
Raquel M Melero-Fernandez de MeraMichael J Courtney

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.

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Citations

Mar 3, 2018·Chemical Society Reviews·Anna V LeopoldVladislav V Verkhusha
Feb 16, 2018·Expert Opinion on Drug Discovery·Michał KiełbusAdolfo Rivero-Müller
Sep 9, 2017·Journal of Molecular Biology·John S KhamoKai Zhang
Jun 4, 2021·Angewandte Chemie·Martin ReyndersDirk Trauner
Jul 10, 2018·Chemical Reviews·Aba LosiAndreas Möglich

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Datasets Mentioned

BETA
KY595935
KY595936
KY595937
KY595938
KY595939
KY595940
KY595941
KY595942
KY595943
KY595944

Methods Mentioned

BETA
GTPase
pulldown
co-immunoprecipitation
PCR
electrophoresis
protein assay
ion exchange chromatography
transfection
transfections

Key Resources (RRID) Mentioned

AB_631936
AB_2313808
AB_331641
AB_10999090
AB_2129572
AB_914102

Software Mentioned

Desmond Molecular Dynamics System
Maestro
Prism
FlexPepDock
Excel Solver
Chimera 68 alpha
NES
OptoJNKi
AttoVision1
ProteoJuice

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