The RUSH (retention using selective hooks) system: a chemical-genetic system for the in vivo manipulation of intercellular communication – VIVORUSH

Complex endocrine circuitries are used to modulate animal physiology. Signals are exchanged constantly between tissues to ensure proper development and adaptation. In particular, metabolism tuning is based on time-controlled release of trophic factors to regulate energy consumption, appetite, fat storage, etc. Here, we will implement a novel way to modulate in real-time such signals in the animal, opening new avenues to manipulate and understand these complex circuits. We will focus our attention on the control of appetite by the ACBP protein. We will adapt the RUSH (Retention Using Selective Hook) system that we have developed to study intracellular trafficking to carry out in vivo studies. In this system, the protein of interest is retained in the endoplasmic reticulum by a reversible, biotin-sensitive interaction. Our preliminary data show that the RUSH system can be deployed in animals. The unconventionally secreted ACBP protein will be adapted to conventional secretion in the RUSH system and its activity controlled by biotin. Different release regimes, and their associated effects at the cellular and whole organism level, will be studied. Beyond the understanding of the functions and mechanisms controlled by ACBP, the VIVORUSH project will allow to set up a generic system allowing to modulate in vivo the release of various hormones and neuroendocrine factors and to study their effects.