Research Interests
Research Summary

T cells respond to external stimuli by adjusting their levels of key regulatory proteins. To accomplish this, T cells can alter protein synthesis or change the rate of protein degradation. "Tagging" a protein with ubiquitin can initiate protein degradation. This process is activated when an E3 ubiquitin ligase transfers ubiquitin to a target protein. While it is known that E3 ubiquitin ligases regulate protein degradation, few details are known regarding when or how these ligases are activated and how they select target proteins. We use genetically engineered mice to study E3 ligase function in vivo and we use biochemical techniques to study protein ubiquitylation and protein fate in vitro.

Currently, our interest centers on two HECT-type E3 ubiquitin ligases, Nedd4 and Itch, and a small family of adaptor proteins, Ndfip1 and Ndfip2. We believe these proteins are uniquely designed to regulate T cell activation and effector differentiation. For example, Nedd4 is needed for T cells to become fully activated while Itch prevents IL-4 production and Th2 differentiation. We recently found that Itch does not function properly in mice that lack Ndfip1. Ndfip1-/- mice develop atopic inflammation at sites of environmental antigen exposure, namely the skin, lung and gastrointestinal tract. This phenotype is strikingly similar to that described for mice lacking Itch. Our data suggest that Ndfip1 acts as an adaptor for Itch. We are currently exploring how Ndfip1 regulates Itch function and are identifying other adaptor/E3 ligase partnerships.

We are also interested in identifying substrates specific for Itch and Nedd4. It is reported that Nedd4 and Itch can ubiquitylate similar substrates in vitro. This implies that these two E3 ubiquitin ligases function similarly. However, this is not supported by the strikingly different phenotypes of mice lacking Itch or Nedd4. We have identified several in vivo substrates for Nedd4 and Itch and we are working to identify others.

Understanding how these E3 ubiquitin ligases and their adaptors function will allow us to design new approaches to regulate these proteins in vivo to treat autoimmune and atopic disease.