Research

Ubiquitin is the basis of a complex and dynamic cellular code that regulates many important biological processes. Ubiquitin modification of a substrate has the potential to initiate a number of diverse regulatory operations – including protein degradation, vesicle trafficking, and cell signaling. Thus, it is critical that this code is written and interpreted with precision. In a cellular context, the syntax of the ubiquitin code and how it contributes to systems-level management of complex processes are still poorly understood. The main research objective of the MacGurn Lab is to understand how ubiquitin modifications regulate important biological processes in eukaryotic cells, and how these mechanisms become dysregulated in disease. By understanding these regulatory mechanisms, we aim to harness the intrinsic cellular ubiquitin conjugation and deconjugation machinery for therapeutic benefit.

Ubiquitin and Membrane Trafficking

Ubiquitin is a major regulator of the trafficking of integral membrane proteins in eukaryotic cells. At the level of the endoplasmic reticulum (ER), ubiquitylation of a substrate results in targeting for ER-associated degradation. At the plasma membrane, ubiquitylation of ion channels, nutrient transporters, and signaling receptors triggers sorting into into budding endocytic vesicles and removal from the cell surface. Our lab is broadly interested in dissecting the regulatory mechanisms that govern these ubiquitylation decisions, since such mechanisms are the foundation for cell surface proteome maintenance as well as remodeling in response to a changing environment.

Ubiquitin and Cellular Stress

When eukaryotic cells encounter environmental stresses that challenge protein folding and stability, ubiquitin reserves are deployed to help the cell. But many facets of this response are not well understood – including how cells manage their ubiquitin reserves and how conjugation machinery are activated. These mechanisms are particularly important for protein quality control, and they come into play during chronological aging of an organism. We aim to contribute to the understanding of how cells remodel ubiquitin pools during cellular stress with the goal of discovering new strategies to “tune up” the ubiquitin network during aging.

Ubiquitin and Signaling

Ubiquitin polymers regulate many important signaling pathways critical for development and disease. This regulation can occur at the level of protein degradation, trafficking, or localization. We are interested in understanding how ubiquitin congjugation and deconjugation machinery are coordinated to implement complex signaling outcomes such as rheostats, which can function in the analog regulation of signaling pathways.