Systemic Regulation of ER Proteostasis

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Abstract Proper activation of cellular stress response pathways allows cells to adapt and maintain homeostasis during stressful conditions. While these pathways are typically thought to be regulated within a cell, recent studies in mice and C. elegans suggest that cellular stress experience in certain cells can distally activate stress response in other tissues. For example, work from our lab have shown that neuronal activation of the endoplasmic reticulum Unfolded Protein Response (UPRER) induces UPRER in the intestine of C. elegans, promoting stress resistance and longevity. These findings clearly demonstrates the importance of systemic regulation of ER proteostasis in organismal health. However, the mechanisms and the signaling molecules underlying such inter-tissue regulation of ER proteostasis remain unknown. Our preliminary work has identified N-acetylglucosamine (GlcNAc), an essential metabolite for protein glycosylation, as a candidate signaling molecule for regulating ER proteostasis across cells. I propose to elucidate mechanisms by which GlcNAc is released by stressed cells and utilized by recipient cells, and to develop novel methods to examine in vivo tissue-to-tissue GlcNAc signaling using neuronal cell culture and C. elegans models. This work will uncover how GlcNAc regulates systemic ER proteostasis, and establish novel techniques to study how sugars and protein glycosylation mediate cell-cell communication.