A simple optogenetic MAPK inhibitor design reveals resonance between transcription-regulating circuitry and temporally-encoded inputs.
Raquel M Melero-Fernandez de MeraLi-Li LiArkadiusz PopinigisKatryna CisekMinna TuittilaLeena YadavAndrius ServaMichael J CourtneyPublished in: Nature communications (2017)
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.
Keyphrases
- induced apoptosis
- signaling pathway
- transcription factor
- cell death
- endoplasmic reticulum stress
- oxidative stress
- energy transfer
- genome wide
- cell cycle arrest
- pi k akt
- protein protein
- amino acid
- heart rate
- copy number
- genome wide identification
- squamous cell carcinoma
- resistance training
- early stage
- sentinel lymph node
- body composition
- climate change
- single cell
- radiation therapy
- quantum dots
- neoadjuvant chemotherapy