RUI: Investigating the mechanisms regulating the formation of lysosome-related organelles

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The project will investigate how compartments are generated within some cell types but not others in multicellular animals. The cells of complex organisms contain compartments called organelles that endow cells with their specific functional properties. While many organelles are common to all of the cells within an organism, some are only generated in a subset of cell types. One of these, called a lysosome-related organelle (LRO), plays varied and important roles, however only certain animal cells generate them. The research will investigate how this is achieved and identify factors that promote the formation of LROs. Many undergraduates (25-55/year)will be mentored in collaborative, investigative, and original research as part of the project. Many of these students will come from underrepresented groups in the sciences. The work will provide hands on scientific training for a large and diverse group of students, most of who will progress on to careers in science and education.In many cell types, lysosome-related organelles LROs co-exist with conventional lysosomes due to the activity of conserved LRO-specific trafficking pathways that divert cargo away from endolysosomes. The emergence of LRO biogenesis pathways likely result from the poorly understood interplay of general endolysosome trafficking factors expressed in all cells with key regulators that are only present and active within LRO-containing cells. To identify and investigate the function of these regulators, the project is analyzing the biogenesis of C. elegans gut granules, cell type-specific LROs that co-exist with conventional lysosomes. Some LRO biogenesis factors identified in this system have cell type restricted expression and likely regulate the diversion of cargo to LROs. The research addresses the function of one of these, GLO-3, which is proposed to redirect the function of CCZ-1, a RAB-7 guanine nucleotide exchange factor (GEF), away from conventional endolysosomal pathways, toward the GLO-1 Rab to regulate LRO biogenesis. The research will involve detailed phenotypic analysis of mutants, yeast 2-hybrid screens, and in vitro GEF assays. The research will examine whether expressing GLO-3 and other LRO biogenesis factors are sufficient to direct the trafficking of LRO cargo away from conventional endosomes in cell types that do not normally generate LROs. The research will employ a novel genetic resource to identify nearly all of the genes necessary for LRO biogenesis in C. elegans.