The endoplasmic reticulum (ER) as a key regulator of metabolism

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Our laboratory investigates proteins that control contacts between intracellular membranes. These contacts communicate a variety of signals and control many cellular functions. The endoplasmic reticulum (ER) forms the best-known intracellular contacts. Our research program aims to understand the functions of these. In this proposal, we investigate how ER contacts determine cellular metabolism and the cellular energy output via mitochondria-ER contacts (MERCs). This key structure for life is controlled by a flow of lipids and Ca2+ ions between the two organelles. Ongoing research from our lab shows this flow is controlled by sensor proteins. Upstream of these sensors are Rab proteins that determine the protein composition of the contact site. These GTPases use the reversible binding to a high energy compound called GTP to either enrich or remove sensor proteins from MERCs. Our preliminary results show that Rab32-mediated localization of sensor proteins to MERCs responds to ER-derived oxidative stress. From our observations, we hypothesize that ER stress and Rab-mediated MERC remodeling cooperate to determine cellular metabolism. In this NSERC application we will test this hypothesis and also investigate the extent of conservation of these functions by introducing the yeast S. cerevisiae as a new model system for our experiments. Our project aims to answer several key questions. Do Rab GTPases respond to a common upstream signal and if so which one? How do such signals control Rabs and the sensor proteins? We propose the following specific aims: 1. How do GTPases respond to ER-derived protein folding stress? We will analyze whether the activity of Rabs changes upon ER protein folding stress. We will test whether these changes depend on Rab post-translational modifications or interactions with guanine nucleotide exchange factors (GEFs). 2. How do MERC membranes transmit ER GTPase activity to mitochondria? We will analyze how ER-influencing GTPases change MERC key properties (proteome, Ca2+ handling and lipidome) and control mitochondria metabolism. 3. Is the transmission of ER metabolic needs to mitochondria conserved? We will analyze yeast for the conservation of our observations and to screen for novel metabolic regulators of MERCs. I expect this proposal to combine yeast and animal model systems to establish a metabolic network based on ER-associated GTPase trafficking proteins. The continuation of our NSERC-funded research program is essential to maintain the first-class training and publication success of high-quality personnel (HQP) of all levels in our lab.