Ticket to Ride: Alpha-arrestin regulation of selective protein trafficking

Cells rapidly reshuffle proteins at the cell surface in response to environmental change, aging and/or protein misfolding; new proteins are sent to the cell surface while those that are no longer functional are selectively removed. How does the cell make the ‘decision’ to change a specific protein’s localization? Knowledge of the factors that drive this cellular decision is critical to human health; nearly 50% of drugs target receptors at the cell surface, highlighting the importance of understanding how membrane protein localization is controlled. The β-arrestins, a well characterized family of trafficking adaptors, control the localization of G-protein coupled receptors (GPCRs) and are themselves therapeutic targets. However, β-arrestins are only a small, recently evolved branch of the much larger arrestin family. The more ancestral α-arrestins, widely conserved but poorly characterized proteins, are the primary focus of my research. Using Saccharomyces cerevisiae as a model, I’ve shown that α-arrestins regulate GPCR signaling and operate in previously unexpected trafficking pathways. In addition, I’ve identified α-arrestin interactions with signaling regulators, membrane proteins and vesicle coat proteins, and have begun to define the molecular mechanisms underlying α-arrestin-mediated trafficking.  All of the α-arrestin-interacting partners I have identified are conserved, and mechanisms for α-arrestin function defined by my work in yeast are proving to be conserved for the mammalian α-arrestins. We are now at the point of transitioning into a mammalian cell system, using our results in yeast to guide targeted studies. Research in my lab employs biochemical, molecular, genetic and advanced cell biology methods to study how α-arrestins regulate membrane protein localization. Our work contributes to emerging paradigms of membrane trafficking and post-ER quality control, and has therapeutic and disease implications.