Molecular mechanisms of membrane protein homeostasis at the Golgi

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Project summary/Abstract The Golgi complex plays a prominent role in secretory and endocytic trafficking in eukaryotic cells and is key to the biosynthesis of glycoconjugates (glycoproteins and glycolipids) that are essential for life. Golgi resident proteins, such as glycosyltransferases and sugar nucleotide transporters, are precisely distributed across the Golgi stacks by recycling mechanisms that counteract the flow of ongoing vesicular transport. Dysfunction in these mechanisms, or their hijacking by viruses and toxins, is known to have serious consequences for human health, leading to congenital disorders of glycosylation, cancers, and immune dysfunction. Membrane proteins residing in various Golgi compartments are well annotated; however, the mecha- nistic basis of how most Golgi proteins are selected for recycling, or how these processes are regulated are poorly understood. My lab is interested in uncovering these fundamental mechanisms governing Golgi homeostasis using a multifaceted approach combining genetics, flow-cytometry, imaging, in vitro reconstitution, and proteomics. In preliminary results, we have identified novel transmembrane compo- nents orchestrating recycling of specific subsets of Golgi enzymes. Our findings have opened doors for interrogating new players and dissecting the mechanisms critical to maintain Golgi identity and function. Over the next five years, our goals are to (1) identify novel recycling receptors required at different Golgi compartments and establish a systematic map of the intra-Golgi recycling network, (2) determine how the transmembrane receptors engage with their cargos, and (3) define the novel functions of a disease- associated membrane transporter in solute transport and protein recycling in the Golgi. The combined results of our experiments will elucidate how multiple recycling pathways sustain normal Golgi function, and how this homeostasis is disrupted in human disease.