NSF/MCB-BSF: Integrating ROS, redox and cell metabolism across plant and animal cells

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Ever since the introduction of oxygen into the atmosphere by photosynthetic organisms, about 2.7 billion years ago, activated forms of oxygen (called reactive oxygen) have been the unwelcome companions of aerobic life. Although currently used by plant and animal cells as important signaling molecules, these activated forms of oxygen could be highly toxic to cells and tissues and cause oxidative injury (oxidative stress). The long-term goal of this project, led by Ron Mittler and Rajeev Azad of the University of North Texas and Rachel Nechushtai of Hebrew University in Jerusalem, Israel, is to determine how cells monitor their intracellular levels of reactive oxygen and prevent its toxicity. In particular, the project will highlight an unknown aspect of the regulation of reactive oxygen in plant and animal cells, namely the use of iron-sulfur clusters by a newly discovered group of proteins to monitor reactive oxygen levels and regulate cellular metabolism and other vital processes. Results obtained from this study could lead to the development of new and novel approaches to enhance the tolerance of crops to important stresses such as drought and heat or delay senescence. In addition, the proposed study could identify novel plant-based compounds and proteins that mitigate oxidative stress, aging and different diseases such as cancer and diabetes. The PIs will train a number of graduate and undergraduate students and partner with a local education center and museum to provide outreach to K-12 students.The PIs will investigate the role of a novel class of Fe-S proteins, NEET proteins, in maintaining ROS homeostasis in plant and animal cells. In light of their unique cluster features, it is hypothesized that NEET proteins use their redox-active labile clusters to sense ROS levels in cells and regulate different pathways that alter cellular metabolism. The Specific Aims of the project are: 1. Perform a comparative signaling and regulatory network analysis of plant and animal cells with altered level and/or function of NEET proteins. 2. Identify the NEET interactome network of plant and animal cells. 3. Determine the dynamics of NEET protein localization/ function in cells and conduct genetic complementation studies of NEET proteins between mammalian and plant cells. Using a combination of functional genetics, proteomics, advanced imaging, RNA-Seq and network analysis approaches, a mechanistic understanding of ROS/redox sensing/regulation in cells will be pursued. The mechanisms identified through this proposed NSF-BSF collaboration will be further compared between different kingdoms: plant - studied through the NSF part, and animal - studied through the BSF part of this project, to obtain an evolutionary perspective of ROS/redox sensing/regulation in cells.This collaborative US/Israel project is supported by the US National Science Foundation and the Israeli Binational Science Foundation.