Are innate immune genes regulators of organismal proteostasis and transcellular chaperone signalling? (360G-Wellcome-200698_Z_16_Z)

In recent years, it has become clear that in the context of multicellular organisms, protein quality control mechanisms are regulated in a cell non-autonomous manner. Using C. elegans I have shown that the regulation of chaperone expression is controlled cell non-autonomously by transcellular chaperone signalling (TCS)1. This inter-tissue signalling in response to a local imbalance of proteostasis adjusts chaperone expression between tissues and has the capability to restore proteostasis in tissues affected by protein misfolding disease. The mechanism of this response is however not understood and the identity of transcellular signalling molecules that mediate TCS are unknown. Using a systems-wide approach I have identified the GATA transcription factor PQM-1 and a set of 27 innate immune genes targeted by PQM-1 as potential mediators of TCS. Therefore, the aims of this proposal are to 1) determine which of the 27 identified innate immune genes are potential mediators of TCS; 2) define a functional basis of how PQM-1 and innate immune genes are involved in the regulation proteostasis, and 3) elucidate the PQM-1 binding profile in stressed animals. This Seed award will establish a strong foundation towards a mechanism of TCS and how it can be used for the treatment of proteinopathies.