Cell non-autonomous function of the unfolded protein response

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DESCRIPTION (provided by applicant): Within invertebrate model organisms such as C. elegans and Drosophila, evidence strongly suggests that tissue-specific manipulations of stress response pathways can affect the aging process of the entire organism. While originating from a single tissue, these manipulations appear capable of propagating synchronous changes to age-related phenotypes across multiple tissues and organs. These compartment-specific stress responses share a role in ensuring maintenance of the proteome, a loss of which would otherwise be catastrophic to the viability of the cell. Because dysfunction in the endoplasmic reticulum (ER) has been associated with a wide-range of age-onset metabolic diseases, including diabetes, obesity, and atherosclerosis, we hypothesized that a restoration of the ER stress response might also have a protective effect on the viability of older animals. We did not know if such a manipulation would affect ER stress response and function cell-autonomously or whether the ER stress response too could be recognized and responded to by distal tissues. Surprisingly, we have discovered that activation of the UPRER in one cell type can also be communicated to a distal cell type that has not undergone ER stress. Using issue specific promoters in the nematode C. elegans that drive expression of spliced version of the UPRER -activating transcription factor XBP-1, we find that neuronal UPR activation can be communicated to distal cells, such as the intestine, resulting in the remote upregulation of ER chaperones. As a consequence, UPRER activation in the nervous system results in increased longevity and stress resistance of the entire animal. This cell non-autonomous response reinforces the idea that in a multi-cellular organism, the sensing of protein folding stress must b conveyed and responded to by the entire organism. The endocrine system is thus an integral and necessary part of multiple conserved cellular stress response pathways. Our data suggest that the UPRER is a cell non-autonomous regulator of age-dependent stress resistance and longevity. We do not yet know the source of this signal, and we do not yet understand the underlying mechanisms of its action. In this proposal, we employ a multi-pronged approach combining genetics, metabolomics, ribosomal profiling, and peptidomics to identify and characterize the signal and its origin. We then use similar techniques to examine the perception of the signal and its consequences in responding tissue. We undertake this research in the hope that novel mechanisms involved in cell non- autonomous UPRER signaling may provide new therapeutic targets for age-onset diseases. We further more hope that such explorations provide valuable insight towards understanding adaptations by which an environmental, extrinsic signal can be sensed and then amplified across the entire animal to coordinate the appropriate onset of reproduction, senescence and/or aging.