The long-term health of all metazoan cells is inextricably linked to protein quality control. An imbalance in protein homeostasis (proteostasis) can result in severe molecular damage to the cell, directly leading to tissue pathology and to enhanced susceptibility to diseases such as neurodegenerative protein misfolding diseases. To maintain cellular proteostasis, cells use ancient stress response mechanisms, such as the heat shock response. These protective protein quality control mechanisms have been known to act cell-autonomously. However, recent evidence in multicellular model organisms, such as the nematode C. elegans show that local protein folding stress triggers such protective mechanisms in the whole organism, by activating and coordinating stress responses between different tissues (Cell. 2013; 153(6): 1366-78). The major objective is to understand at the molecular level how tissues coordinate stress response mechanisms to maintain organismal health. Our hypothesis is that stress resistant animals have unique stress gene expression profiles in the sender tissue that experiences protein folding stress, and in receiving tissues that induce stress response mechanisms. To determine gene expression and regulatory features in the individual tissues required for transcellular stress signaling, we will use tissue-specific transcriptome (RNA-seq) and chromatin profiling (ChIP-Seq) along with functional assays and high resolution fluorescence microscopy. Comparison with expression profiles in C. elegans disease models such as Huntington’s disease, will allow for the identification of unique regulatory “transcellular” components that may be harnessed to prevent the onset of protein misfolding disease. This will have a potentially broad impact across areas of biology and medicine for the treatment of neurodegenerative protein misfolding diseases.
For further information see:
van Oosten-Hawle, P., Porter, R.S., and Morimoto, R.I. ; Regulation of organismal proteostasis by transcellular chaperone signaling. Cell 2013, 153, 1366-1378.
van Oosten-Hawle, P. and Morimoto, R.I. Organismal Proteostasis: Role of cell nonautonomous regulation and intertissue stress signaling. Genes & Development. 2014 Jul 15; 28(14):1533-1543.
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