Immunology Graduate Group
Paula M. Oliver, Ph.D.
Assistant Professor, Pathology
Address: 816F Abramson Research Center
Office Phone: (267) 426-2839
Lab Phone: (267) 426-0292
Fax: (267) 426-5165
Email: paulao@mail.med.upenn.edu
Education
Ph.D., Pathology, UNC-Chapel Hill
B.S., Zoology, NCSU
Research Interest
Nedd4-family ubiquitination networks that regulate T cell activation and tolerance.
Research Summary
T cells respond to external stimuli by adjusting their levels of key regulatory proteins. To accomplish this, T cells must 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 these 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 make geneticly engineered mice to study E3 ligase function in vivo and we use biochemical and cell imaging to study protein/protein interactions in vitro.
Our interest centers on two HECT-type E3 ubiquitin ligases, Nedd4 and Itch, and a small family of binding proteins, Ndfip1 and Ndfip2. We believe these proteins are uniquely designed to regulate T cell tolerance and activation. We recently described a novel mechanism for regulating Itch. We found that Itch does not function properly in mice that lack Ndfip1. Ndfip1-/- mice have inflamed lungs and develop a disease that resembles atopic dermatitis. This phenotype is reminiscent of that described for mice lacking Itch. Ndfip1 is one of a growing number of proteins that have been identified because of their ability to bind Nedd4 family members. Based on our results from studying Ndfip1, we believe these binding proteins act as scaffolds to regulate Nedd4-family E3 ubiquitin ligases. We are currently exploring how these binding proteins regulate Nedd4 and Itch function and would like to identify the relevant binding protein/E3 ligase partnerships.
We are also interested in identifying target proteins specific for Itch and Nedd4. It is reported that Nedd4 and Itch can ubiquitinate similar target proteins. This implies that these two E3 ubiquitin ligases function similarly. This turns out not to be the case. We recently found that T cells lacking Nedd4 proliferate and produce cytokine poorly in response to antigen in vivo (quite the opposite phenotype to that reported for Itch mutant mice). We have identified one Nedd4 target that supports this phenotype but we believe that there may be others.
Understanding how these E3 ubiquitin ligases function will allow us to design new approaches to regulate these proteins in vivo to treat autoimmune and atopic disease.
Recent Publications
Oliver PM, Yang B, Kappler J, Marrack P, Nedd4-1 augments the adaptive immune response by promoting ubiquitin-mediated degradation of cbl-b in activated T cells. Manuscript in preparation.
Oliver PM, Cao X, Worthen GS, Peijun S, Briones N, MacLeod M, White J, Kirby P, Kappler J, Marrack
P, Yang B. Ndfip1 protein promotes the function of Itch ubiquitin ligase to prevent T cell
activation and T helper 2 cell-mediated inflammation. Immunity 2006 Dec;25(6) 25, 929-40.
Oliver PM, Vass T, Kappler J, Marrack P. Loss of the proapoptotic protein, Bim, breaks B cell anergy. J Exp Med. 2006 March 6, 203(3) 731-41.
Oliver PM, Wang M, Zhu Y, White J, Kappler J, Marrack P. Loss of Bim allows precursor B cell survival but not precursor B cell differentiation in the absence of interleukin 7. J Exp Med. 2004 Nov 1;200(9):1179-87.
Lab Personnel
Denise Gay
Tamara Hala
Biomedical Graduate Studies | University of Pennsylvania | Contact