One of the major recent discoveries in the field of proteostasis, is the finding that protein quality control mechanisms in multicellular organisms are communicated between different tissues. Using C. elegans, I have shown that the regulation of chaperone expression is controlled cell-nonautonomously by transcellular chaperone signalling (TCS). A key observation of TCS is that mild tissue-specific stress, results in a compensatory activation of cyto-protective hsp-90 and hsp-70 chaperone expression in other tissues. Thus TCS has the potential to restore proteostasis in tissues affected by protein misfolding disease, such as neurodegenerative diseases. The mechanism of TCS is however not understood, and the "transcellular signaling factor" that is transmitted between tissues is unknown.
Using a system-wide approach and genetic analysis, I have identified the conserved transcription factor PQM-1, and a conserved secreted immune peptide (asp-12) targeted by PQM-1 as potential mediators of TCS. The precise role of this transcription factor and asp-12 in the regulation of organismal proteostasis and TCS is not understood. The objectives of this proposal are to: 1.) elucidate the PQM-1 chromatin binding profile during heat stress and tissue-specific stress that activates TCS; 2.) define a mechanistic basis of how PQM-1 and ASP-12 regulate TCS and the activation of chaperone expression between tissues; and 3.) establish C. elegans as a translatable model system, to investigate how TCS-mediated activation of chaperone expression restores proteostasis in tissues affected by protein misfolding diseases.
The immediate outcome will provide the underlying mechanism for TCS and establish asp-12 as a "transcellular signaling molecule". The C. elegans chaperone reporters will replace the use of mouse neurodegenerative disease models, to understand how TCS can be harnessed to restore proteostasis in tissues affected by protein misfolding diseases.
Kleinhappel T et al. (2019). Expanding the Organismal Proteostasis Network: Linking Systemic Stress Signaling with the Innate Immune Response. Trends in Biochemical Sciences 44(11):927-42. doi: 10.1016/j.tibs.2019.06.009
O'Brien D et al. (2018). A PQM-1-Mediated Response Triggers Transcellular Chaperone Signaling and Regulates Organismal Proteostasis. Cell Reports 23(13):3905–3919. doi: 10.1016/j.celrep.2018.05.093