An Nrf1- and Nrf2-related Transcription Factor, Cnc-C, Mediates Multiple Stress Responses in Drosophila Melanogaster PDF Download

Author: Min Tian
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Languages : en
Pages : 144

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Book Description
Ineffective cellular stress responses contribute to the development of multiple diseases. A family of the highly conserved transcription factors represented by Cnc proteins in Drosophila and Nrf proteins in mammals includes important mediators of such stress responses. One such protein, mammalian, Nrf2, is a master regulator of oxidative stress defense genes. The related Nrf1 protein, in contrast plays an important role in preventing or ameliorating unfolded protein stress and maintaining effective proteasomal protein degradation. The cap’n’collar (cnc) gene encodes the sole member of this family in Drosophila. Work by the Bohmann lab has previously shown the Cnc C-splice form, CncC, to be a functional homolog of Nrf2 and to regulate the expression of many antioxidant genes in response to oxidative stress. No other cnc family gene is present in the Drosophila genome and whether a fly homolog of Nrf1 exists had remained unclear. I and others, however, noticed, sequence similarities between CncC and Nrf1, raising the possibility that the Drosophila cnc locus encodes one or several proteins that combine the functions of Nrf1 and Nrf2. Here, I provide evidence in support of this hypothesis. I show that CncC mediates the transcriptional response to oxidative stress and proteasome dysfunction by two distinct mechanisms. I show that the activation of CncC in response to impaired proteasome function requires the aspartic protease Rings Lost (Rngo) and Nglycanase 1 (Ngly1). Intriguingly, since a recessive mutation of the human ngly1 gene is the cause of a rare neurological syndrome (N-glycanase deficiency), loss of Nrf1 function may contribute to the pathology of this disease. My work establishes Drosophila CncC as an interesting model to study the interplay and coordination of the cellular responses to proteotoxic and oxidative stresses. Taking advantage of the Drosophila system to investigate the biology of the Nrf protein family may thus contribute to the understanding of human diseases that are associated with cellular stress, possibly including N-glycanase deficiency. The second chapter of my thesis focuses on the relationship between high sugar diet, obesity and oxidative stress. It has been shown that obesity is associated with increased oxidative stress in multiple tissues. This increased oxidative stress can be caused by either increased ROS production or decreased antioxidant mechanisms. While it has been shown that overnutrition increases ROS production in mitochondria, how nutrition surplus affects antioxidant defense pathways is less well understood. I hypothesized that nutrition surplus compromises the oxidative stress defense. To explore this idea, I established an obesity model in which Drosophila is exposed to a high-sucrose diet. Consistent with the starting hypothesis, I found that high-sucrose food suppresses the fly’s oxidative stress defense. Further experiments are needed to understand the molecular mechanism by which high-sucrose diet reduces antioxidant responses. My experiments establish a connection between high-sucrose diet and oxidative stress defense and demonstrate the advantage of using the fruit fly as an animal model to study the health effects of obesity and related metabolic diseases.