Synopsis. We describe herein a series of non-opsin based optogenetic tools tailored for remote control of cell signaling in mammals. Existing tools are either derived from engineered channelrhodopsin variants without strict Ca2+ selectivity or based on engineered GPCRs that might crosstalk with other signaling pathways. We introduce three different approaches to confer photosensitivity to STIM1 and ORAI as the two essential components for the calcium release-activated (CRAC) channel. These genetically-encoded calcium channels or actuators (GECAs) display biophysical features reminiscent of the ORAI1 channel, which enables precise optical control over Ca2+ signals and hallmark Ca2+-dependent physiological responses. GECAs can be further coupled with upconversion nanoparticles to enable wireless optogenetics in vivo, a technology that can be readily extended to optogenetic dissection of CNS without optical fiber implantation in the brain. We demonstrate the use of GECAs to modulate anti-cancer immune response and intervene in neurodegeneration in a Drosophila model of amyloidosis. Similar nano-optogenetic approaches have been extended to photo-control immunogenic cell death (pyroptosis and necroptosis) and STING signaling, as well as the design of light-switchable chimera antigen receptor (LiCAR) T-cells for precision immunotherapy against both blood cancers and solid tumors. This hybrid nano-optogenetic immunomodulation platform not only provides a unique approach to interrogate immune cell-mediated anti-tumour immunity, but also sets the stage for developing precision medicine to deliver personalized anticancer therapy. If time allowed, I will also briefly present several new chemogenetic to remotely control proteins and therapeutic cells.
Student Host: Andrew Huang (Kai Zhang lab), The MCB/Biophysics Graduate Fellowship
