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Our research is driven by the desire to understand how the organelles of the endomembrane system - the collection of intracellular, membrane-bounded organelles that compartmentalize the biochemical reactions that fuel life - are assembled and maintained. The endomembrane system is broadly divided into the secretory pathway, which is responsible for the production and distribution of newly synthesized molecules throughout the cell, and the endocytic system, which internalizes components of the extracellular milieu and the plasma membrane. Elucidating the mechanisms that sort molecules to various organelles is of fundamental importance for understanding cell growth, division, multi-cellular development and physiology, and it is also crucial for understanding a broad range of diseases and afflictions - cancer, neurodegenerative disease, infectious disease, and many others. Phosphoinositide and GTPase signaling modules constitute the master regulators of organelle biogenesis.

Phosphoinositides (“PIPs”) are generated by phosphorylation of distinct positions on the inositol ring of phosphatidylinositol, an abundant lipid of all cellular membranes. Importantly, the cytoplasmic leaflet of each organelle is enriched in a different PIP, constituting an organelle specific PIP code. Similarly, distinct GTPases of the Rab and Arf families associate with distinct organelles and the transport vesicles that ferry molecules between them. Specific recognition of PIPs and GTPases by sorting and transport factors regulate the composition and identity of each organelle by regulating inter-organelle transport. In our lab we harness yeast genetics/genomics, proteomics, biochemistry, and live cell fluorescence microscopy to elucidate the molecular mechanisms of these sorting and trafficking pathways.

Research

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The eukaryotic cell is compartmentalized by membrane-bounded organelles that carry out linked biochemical reactions that sustain life. We investigate how the activities of the biosynthetic secretory and the endocytic pathways respond to metabolic, physiological, and environmental cues to effect rapid and specific changes in inter-organelle trafficking focusing the on the Golgi apparatus, the plasma membrane, and the endosome.

Left: Live cell fluorescence microscopy of a HeLa cell showing trafficking of a GFP-tagged secretory protein (Syndecan-1) through the secretory pathway. A protein of the Golgi apparatus appears in magenta.  Images by Yeongho Kim, Ph.D.

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Nearly all proteins and lipids that are secreted  are produced in the endoplasmic reticulum and transported to and through the Golgi apparatus, whose multiple compartments (cisternae) contain enzymes that sequentially modify the secretory 'cargo' (lipids and proteins). Once the modifications to secreted cargo are completed, they are packaged into transport vesicles that bud the terminal compartments of the Golgi - the trans cisternal and the trans-Golgi network (TGN) - and ferry their cargo to its resident organelle. We investigate how lipid and protein trafficking out of the Golgi are linked to maintain organelle composition.

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The plasma membrane is a selective barrier between the cell and its environment, yet each hour the equivalent of the entire cell plasma membrane is internalized to the endo-lysosomal system, consisting of endosomes and the lysosome (or the lysosome-like vacuole in yeast cells) by the process of endocytosis . More than 90% of these lipids and proteins are returned/recycled to the plasma membrane minutes after internalization, while others are sorted into the lysosomal degradative pathway. We investigate how the ‘recycle or degrade’ decision controls the repertoire of nutrient transport proteins, ion transporters, cell adhesion molecules, signaling receptors, and other molecules – to be changed in response to changes in nutrient availability, chemical cues, mitogenic signals, while still maintaining the physical attributes of the plasma membrane. 

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