Paula M Oliver, PhD
Children’s Hospital of Philadelphia
The University of Pennsylvania
3615 Civic Center Blvd. 816F/ARC
Philadelphia, PA 19104
North Carolina State University, 1989.
University of North Carolina at Chapel Hill, 1998.
Description of Research ExpertiseResearch Interest
Our focus is on defining new mechanisms that regulate immune cell activation and protective immune responses. Our goal is to use this information to design therapies with which to treat the immune-mediated pathologies found in autoimmune and allergic disease.
During pathogenic infection, immune cells collaborate to remove invading organisms while minimizing collateral damage. Immune cells must continually respond to external stimuli, and adjust their levels of key regulatory proteins, to transition between poised and active states. To accomplish this, immune cells can increase protein production, modify existing proteins, or change their rate of protein degradation. ‘Tagging’ a protein with ubiquitin is a post-translational modification that can improve interactions between proteins to promote signaling, or initiate protein degradation. Ubiquitylation is regulated by enzymes that add (E3 ubiquitin ligases) or subtract (deubiquitylating enzymes) ubiquitin from substrates. We use systems biology approaches to define changes in ubiquitylation as activation states change, and to identify ubiquitin ligases that regulate immune cell fate. We combine this information with genetic, cellular and biochemical approaches to define how ubiquitin enzymes regulate immune cell biology.
One area of focus in the lab has centered on catalytic HECT-type E3 ubiquitin ligases of the Nedd4-family. The 9 members of this family that exist in mammalian cells evolved from a common yeast progenitor known as RSP5. We have identified a small family of membrane tethered adaptors, Ndfip1 and Ndfip2, that activate several Nedd4-family E3s. Additionally, we have determined that these adaptors regulate T cell activation, CD4 differentiation and effector function, and Treg cell metabolism and lineage stability. We combined this information on biologic function with biochemical data in which we defined precisely how these adaptors activate the enzymatic activity of Nedd4-family ligases, and are now using this information in the rational design of therapeutics. Based on our data, such therapeutics will be particularly useful in the treatment of autoimmune and/or allergic disease.
Our recent work has employed systems biology approaches in which we intrgrated transcriptome, proteome and ubiquitome information to identify Cullin E3 ubiquitin ligases that are particularly active as T cells transition from resting to activated states. We are now generating genetic models in which to test the the biologic relevance of these ligases in protective immune responses. We are now poised to define how cullin ligases form distinct ubiquitin complexes in T cells or other immune cells, and the unique set of substrates targeted by these complexes. Once we answer these questions we will be positioned to translate this information into new therapies for patients.
Emily Moser PhD – Postdoctoral Fellow
Awo Layman – MD/PhD Student (IGG)
Natania Field – MD/PhD Student (MVP)
Asif Dar PhD – Postdoctoral Fellow
Joseph Dybas PhD – Postdoctoral Fellow
Yan Chen PhD – Technician
Keisuke Sawada – Technician
Jennifer Roof – Undergraduate
Varshini Gali - Undergraduate
Selected PublicationsEmily Moser, Jennifer Roof, Joseph Dybas, Lynn Spruce, Steve Seeholzer, Michael Cancro, and Paula Oliver.: The E3 ubiquitin ligase Itch restricts antigen-driven B cell responses. Journal of Experimental Medicine 216(9): 2170, September 2019.
Joseph M. Dybas, Claire E. O’Leary, Hua Ding, Lynn A. Spruce, Steve H. Seeholzer and Paula M. Oliver : Integrative proteomics reveals that CD4+ T cell activation promotes non-degradative ubiquitylation. Nature Immunology 20(6): 747, June 2019.
Emily Moser and Paula M. Oliver: Regulation of Autoimmune Disease by the E3 Ubiquitin Ligase Itch. Cellular Immunology June 2019.
Emily K Moser, Natania S Field and Paula M Oliver: Aberrant Th2 inflammation drives dysfunction of alveolar macrophages and susceptibility to bacterial pneumonia. Cellular & Molecular Immunology 15(5): 480-492, May 2018.
Awo Akosua K. Layman, Guoping Deng, Claire E. O’Leary, Samuel Tadros, Rajan M. Thomas, Joseph M. Dybas, Emily K. Moser, Andrew D. Wells, Nicolai M. Doliba & Paula M. Oliver: Ndfip1 restricts mTORC1 signaling and glycolysis in regulatory T cells to prevent autoinflammatory disease. Nature Communications 8: 15677, June 2017.
Awo AK Layman, Stephanie Sprout, Dylan Phillips, and Paula M Oliver.: Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production. Sci Reports 4(7): 39649, Jan 2017.
Awo Layman and Paula Oliver: Ubiquitin ligases and Dubs in CD4+ T cell effector fate choice and function. Journal of Immunology 196(10): 3975-82, May 2016.
Claire E. O'Leary, Christopher Riling, Lynn Spruce, Hua Ding, Suresh Kumar, Guoping Deng, Yuhong Liu, Steven H. Seeholzer, and Paula M. Oliver: Ndfip-mediated degradation of Jak1 tunes cytokine signaling to limit expansion of CD4+ effector T cells. Nature Communications 18(7): 11226, April 2016.
Christopher Riling, Hari Kamadurai, Suresh Kumar, Claire E. O’Leary, Kuen-Phon Wu, Erica E. Manion, Mingjie Ying, Brenda A. Schulmanb, and Paula M. Oliver: Itch WW domains inhibit its E3 ubiquitin ligase activity by blocking E2-E3 transthiolation. Journal of Biological Chemistry 290(39): 23875-87, Sept 2015.
Allison M. Beal, Natalia Ramos-Hernandez, Chris R. Riling, Erin A. Nowelsky and Paula M. Oliver: TGF-β induces the expression of the adaptor Ndfip1 to silence IL-4 production during iTreg cell differentation. Nature Immunology 13(1): 77-85, January 2012 PMCID: PMC3542978.