Reference number : GC-2017-Q1-03246, amendment number : , agreement type : G, recipient legal name : Willmore, William (Carleton University), recipient country : CA, recipient province : nan, recipient city : Ontario, recipient postal code : nan, program name english : Discovery Grants Program - Individual, program name french : Programme de subventions à la découverte - individuelles, program purpose english : Organisms must respond to a broad array of stresses which they may encounter during their lifespan. Stresses often occur, not as a single occurrence, but as multiple stresses which impinge upon the organism simultaneously. Stresses such as toxin stress, oxidative stress, low oxygen (hypoxic) stress and endoplasmic reticulum (ER) stress often occur concurrently. &ldquo;Crosstalk&rdquo; between multiple stresses often involves common protein factors which respond to a variety of extra- and intra-cellular signals. My research program focuses on one such protein that responds to multiple signalling processes and examines how these signals interact, either synergistically or antagonistically, to affect its function. Nuclear factor erythroid 2 like 1 (NFE2L1 or Nrf1) is a "cap'n'collar" basic leucine zipper transcription factor that heterodimerizes with small Maf proteins and bind to a DNA element known as the Antioxidant Response Element/Electrophile Response Element, required to transactivate antioxidant enzyme, phase 1 and 2 detoxification enzyme and proteasome subunit gene expression. Nrf1 responds to oxidative stress and regulates pathways involved in lipid metabolism, amino acid metabolism, proteasomal degradation, the citric acid cycle, and the mitochondrial respiratory chain. An unanswered question is the possibility that Nrf1 may also respond to ER stress, but how this occurs and how environmental stresses (toxin stress, hypoxia, oxidative stress) work in tandem with ER stress to affect Nrf1 function remains to be investigated. We recently demonstrated that a) hypoxia affects the way that Nrf1 is proteolytically processed, b) various environmental toxins affect the translocation of Nrf1 to the nucleus and c) phosphorylation of key tyrosines on the protein affect its ubiquitination and anchoring to the ER. The aims outlined in this proposal set out to demonstrate that cross-talk occurs between multiple environmental stressors and ER stress on Nrf1 function in mammalian cells. Aim 1 will examine the factors responsible for the proteolytic processing of Nrf1 and how these are altered by environmental stresses. Aim 2 will focus on stress-dependent post-translational modifications of the Nrf1 protein that affect its glycosylation, proteolytic processing and release from the ER under different stress conditions. Aim 3 will investigate the cross-talk between environmental stresses with ER stress in activating Nrf1. My long-term goals are to illustrate the importance of Nrf1 in the response to a broad range of cellular stresses and how these stresses act to affect its a) post-translational modification, b) release from the ER and translocation to the nucleus, c) proteolytic processing as well as determining whether multiple extra- and intracellular signals act synergistically or antagonistically on Nrf1. Similar mechanisms may apply to a number of different stress-response proteins., program purpose french : Organisms must respond to a broad array of stresses which they may encounter during their lifespan. Stresses often occur, not as a single occurrence, but as multiple stresses which impinge upon the organism simultaneously. Stresses such as toxin stress, oxidative stress, low oxygen (hypoxic) stress and endoplasmic reticulum (ER) stress often occur concurrently. &ldquo;Crosstalk&rdquo; between multiple stresses often involves common protein factors which respond to a variety of extra- and intra-cellular signals. My research program focuses on one such protein that responds to multiple signalling processes and examines how these signals interact, either synergistically or antagonistically, to affect its function. Nuclear factor erythroid 2 like 1 (NFE2L1 or Nrf1) is a "cap'n'collar" basic leucine zipper transcription factor that heterodimerizes with small Maf proteins and bind to a DNA element known as the Antioxidant Response Element/Electrophile Response Element, required to transactivate antioxidant enzyme, phase 1 and 2 detoxification enzyme and proteasome subunit gene expression. Nrf1 responds to oxidative stress and regulates pathways involved in lipid metabolism, amino acid metabolism, proteasomal degradation, the citric acid cycle, and the mitochondrial respiratory chain. An unanswered question is the possibility that Nrf1 may also respond to ER stress, but how this occurs and how environmental stresses (toxin stress, hypoxia, oxidative stress) work in tandem with ER stress to affect Nrf1 function remains to be investigated. We recently demonstrated that a) hypoxia affects the way that Nrf1 is proteolytically processed, b) various environmental toxins affect the translocation of Nrf1 to the nucleus and c) phosphorylation of key tyrosines on the protein affect its ubiquitination and anchoring to the ER. The aims outlined in this proposal set out to demonstrate that cross-talk occurs between multiple environmental stressors and ER stress on Nrf1 function in mammalian cells. Aim 1 will examine the factors responsible for the proteolytic processing of Nrf1 and how these are altered by environmental stresses. Aim 2 will focus on stress-dependent post-translational modifications of the Nrf1 protein that affect its glycosylation, proteolytic processing and release from the ER under different stress conditions. Aim 3 will investigate the cross-talk between environmental stresses with ER stress in activating Nrf1. My long-term goals are to illustrate the importance of Nrf1 in the response to a broad range of cellular stresses and how these stresses act to affect its a) post-translational modification, b) release from the ER and translocation to the nucleus, c) proteolytic processing as well as determining whether multiple extra- and intracellular signals act synergistically or antagonistically on Nrf1. Similar mechanisms may apply to a number of different stress-response proteins., agreement title english : Signaling Cross-talk Between Endoplasmic Reticulum And Oxidative Stresses, agreement title french : Signaling Cross-talk Between Endoplasmic Reticulum And Oxidative Stresses, agreement number : RGPIN, agreement value : 170000.0, agreement start date : 2017-05-10, agreement end date : nan, description english : nan, description french : nan, expected results english : nan, expected results french : nan, additional information english : Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023), additional information french : Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier. (2017-2018 à 2022-2023), owner organization : nserc-crsng, owner organization title : Natural Sciences and Engineering Research Council of Canada | Conseil de recherches en sciences naturelles et en génie du Canada