Dopamine Signaling Activates The UPS In Distal Epithelial Tissues

The Ubiquitin Proteasome System (UPS) is a key mechanism by which cells maintain protein homeostasis (proteostasis) by removing misfolded and oxidized proteins. This system comprises many ubiquitin ligases, which tag individual proteins for degradation by the 26S Proteasome. As cells age, UPS activity becomes impaired, resulting in the accumulation of damaged proteins and age-associated physiological decline. By understanding how UPS activity is regulated in neurons and in non-neuronal tissue by neurons, we should be able to provide new therapeutic targets for diseases that involve protein aggregates and disrupted proteostasis.  We previously generated a GFP-based reporter system for UPS activity in C. elegans, allowing us to query UPS activity in specific tissues and at specific points along development. We found that epithelial cells undergo a dramatic increase in UPS activity as animals mature. We have also found that the humoral neurohormone/biogenic amine neurotransmitter dopamine promotes UPS activity in epithelia. In C. elegans, mechanosensory neurons release dopamine when nematodes encounter a potential bacterial food source. Dopamine in turn inhibits motoneuron activity through the dopamine receptors DOP-2 and DOP-3, resulting in a behavioral change that slows the animal down so that it can feed. We found that this released dopamine also activates the UPS in epithelial tissues, including the intestine and epidermis, through the dopamine receptors DOP-1 and DOP-4, and the cAMP-Response Element Binding Protein (CREB) transcription factor. This signaling pathway activates the expression of enzymes involved in xenobiotic detoxification (e.g., cytochrome P450 enzymes) and innate immunity, which in turn promote protein polyubiquitin. Although we do not yet understand exactly how xenobiotic detoxification activates the UPS, our results show that dopamine signaling is essential for nematodes to survive xenobiotic stress and to maintain normal proteostasis. Taken together, our results suggest that dopaminergic sensory neurons, in addition to slowing down locomotion upon sensing a potential bacterial feeding source, also signal to epithelial tissues to prepare for infection in case that potential bacterial food source turns out to be pathogenic.

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Dopamine signaling promotes the xenobiotic stress response and protein homeostasis.

Joshi KK, Matlack TL, Rongo C. EMBO J. 2016 Sep 1;35(17):1885-901. doi: 10.15252/embj.201592524. Epub 2016 Jun 3.  PMID: 27261197

Multicellular organisms encounter environmental conditions that adversely affect protein homeostasis (proteostasis), including extreme temperatures, toxins, and pathogens. It is unclear how they use sensory signaling to detect adverse conditions and then activate stress response pathways so as to offset potential damage. Here, we show that dopaminergic mechanosensory neurons in C. elegans release the neurohormone dopamine to promote proteostasis in epithelia. Signaling through the DA receptor DOP-1 activates the expression of xenobiotic stress response genes involved in pathogenic resistance and toxin removal, and these genes are required for the removal of unstable proteins in epithelia. Exposure to a bacterial pathogen (Pseudomonas aeruginosa) results in elevated removal of unstable proteins in epithelia, and this enhancement requires DA signaling. In the absence of DA signaling, nematodes show increased sensitivity to pathogenic bacteria and heat-shock stress. Our results suggest that dopaminergic sensory neurons, in addition to slowing down locomotion upon sensing a potential bacterial feeding source, also signal to frontline epithelia to activate the xenobiotic stress response so as to maintain proteostasis and prepare for possible infection.

EGF signalling activates the ubiquitin proteasome system to modulate C. elegans lifespan.

Liu G, Rogers J, Murphy CT, Rongo C. EMBO J. 2011 Jun 14;30(15):2990-3003. doi: 10.1038/emboj.2011.195. PMID:21673654

Epidermal growth factor (EGF) signalling regulates growth and differentiation. Here, we examine the function of EGF signalling in Caenorhabditis elegans lifespan. We find that EGF signalling regulates lifespan via the Ras-MAPK pathway and the PLZF transcription factors EOR-1 and EOR-2. As animals enter adulthood, EGF signalling upregulates the expression of genes involved in the ubiquitin proteasome system (UPS), including the Skp1-like protein SKR-5, while downregulating the expression of HSP16-type chaperones. Using reporters for global UPS activity, protein aggregation, and oxidative stress, we find that EGF signalling alters protein homoeostasis in adults by increasing UPS activity and polyubiquitination, while decreasing protein aggregation. We show that SKR-5 and the E3/E4 ligases that comprise the ubiquitin fusion degradation (UFD) complex are required for the increase in UPS activity observed in adults, and that animals that lack SKR-5 or the UFD have reduced lifespans and indications of oxidative stress. We propose that as animals enter fertile adulthood, EGF signalling switches the mechanism for maintaining protein homoeostasis from a chaperone-based approach to an approach involving protein elimination via augmented UPS activity.