Paula M. Oliver, PhD
Associate Professor of Pathology and Laboratory Medicine
University of Pennsylvania Perelman School of Medicine
Contact InformationCell Pathology Division 816F/ARC
Children’s Hospital of Philadelphia
The University of Pennsylvania
3615 Civic Center Blvd. 816F/ARC
Philadelphia, PA 19104
Immunobiology and Experimental Pathology
Nedd4-family ubiquitylation networks that regulate T cell activation and effector differentiation.
During pathogen infection, T cells orchestrate the immune response to eliminate the pathogen and prevent collateral damage. To do this, T cells must continually respond to external stimuli and adjust 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. Additionally, we use biochemical techniques to study protein ubiquitylation and protein fate in vitro.
Currently, our interest centers on a family of catalytic HECT-type E3 ubiquitin ligases, termed the Nedd4-family. The 9 members of this family that exist in mammalian cells evolved from a common yeast progenitor known as RSP5. Additionally, we study a small family of membrane tethered Nedd4-family interacting proteins, Ndfip1 and Ndfip2, that have little relatedness to other proteins in the mammalian genome.
We have shown previously that certain Nedd4-family E3 ubiquitin ligases promote T cell activation, while others inhibit effector differentiation and cytokine production. For example, the prototypic family member Nedd4 is needed for T cells to become fully activated, while another Nedd4-family E3 ligase, Itch, prevents IL-4 production and Th2 differentiation. Furthermore, we have determined that certain Nedd4-family members rely on Ndfip1 and Ndfip2 to function. For example, Itch requires Ndfip1 to ubiquitylate substrates. Supporting this, both Itch-deficient and Ndfip1-/- mice develop TH2-mediated inflammation at mucosal barrier sites such as skin, lung and gut. Our current work is focused on defining how Ndfip proteins promote E3 ligase function in vivo and in vitro.
We are now characterizing other Ndfip/Nedd4 E3 ligase partnerships and probing the biologic consequence of the formation and activation of these ubiquitylation complexes. These studies are likely to reveal new substrates that are ubiquitylated by such complexes.
Understanding the context and consequence of these ubiquitin complexes will allow us to design therapeutic approaches for tuning ubiquitylation in disease settings. Based on our data from mouse models, this approach may be particularly useful to treat inflammation and allergic disease.
Chris Riling-Graduate Student (CBP)
Allison Beal-Postdoctoral Fellow
Vanessa Kurzwiel-Graduate Student (MVP)
Natalia Ramos-Hernandez-Graduate Student (IGG)
Ami Laroche-Research Technician
Claire O'Leary-Graduate Student (CBP)
T cell differentiation
T cell function
Cell and Molecular Biology
BS (Zoology), North Carolina State University, 1989
PhD (Pathology), University of North Carolina at Chapel Hill, 1998
Postdoctoral Fellowship-Immunology, National Jewish Medical and Research Center, 1998-2002
Postdoctoral Fellowship - Immunology, HHMI National Jewish Medical and Research Center, 2002-2007
Awards and Honors
NIH Postdoctoral Training Grant, 1998-1999
Leukemia and Lymphoma Society Fellow, 1999-2002
Christopher and Peter Gitzen Fellowship, 2000-2001
Howard Hughes Medical Institute, 2002-2005
Foerderer Award, 2008-2009
Chair Research Award, 2009-2010
ITMAT Award, 2013-2015
American Asthma Association Scholars Award, 2013-2016
Memberships and Professional Organizations
National Jewish Center, 2002 - 2003
American Association of Immunologists, 2009 - present
Arthritis Foundation post-doctoral training grants, 2010 - 2010
Annual Ubiquitin Research in Drug Discovery Conference, 2012 - 2013
Faculty 1000, 2012 - present
National Institutes of Health, hypersensitivity, autoimmunity, immune-mediated (HAI) study section, 2012 - 2014
NIH Immunology Fellowships and Area Study Section, 2012 - 2014
National Institutes of Health, hypersensitivity, autoimmunity, immune-mediated (HAI) study section, 2014 - Present
Ubiquitin ligases and Dubs in CD4+ T cell effector fate choice and function
Awo Layman and Paula Oliver, Journal of Immunology 196(10): 3975-82, 2016
Ndfip-mediated degradation of Jak1 tunes cytokine signaling to limit expansion of CD4+ effector T cells
Claire E. O'Leary, Christopher Riling, Lynn Spruce, Hua Ding, Suresh Kumar, Guoping Deng, Yuhong Liu, Steven H. Seeholzer, and Paula M. Oliver, Nature Communications 18(7): 11226, 2016
Ubiquitylation as a rheostat for TCR signaling: from targeted approaches towards global profiling
Claire E. O’Leary, Emma L. Lewis, and Paula M. Oliver, Frontiers in Immunology 16(6): 618, 2015
Itch WW domains inhibit its E3 ubiquitin ligase activity by blocking E2-E3 transthiolation
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, Journal of Biological Chemistry 290(39): 23875-87, 2015
Vanessa Kurzweil, Ami Laroche, and Paula M. Oliver, Journal of Immunology 20(5): 524-30, 2014, PMID:24747744
The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice.
Deshmukh H., Liu Y., Menkiti O., Mei J., Dai N., O’Leary C., Oliver P.M., Kolls J., Weiser J., and Worthen G.S., Nature Medicine 20(5): 524-30, 2014
Ndfip1 enforces a requirement for CD28 co-stimulation by limiting IL-2 production.
Natalia Ramos-Hernández, Hilda E. Ramon, Allison M. Beal, Ami Laroche, Erin A. Dekleva and Paula M. Oliver, Journal of Immunology, 2013 PMCID: PMC3853121
TGF-β induces the expression of the adaptor Ndfip1 to silence IL-4 production during iTreg cell differentation
Allison M. Beal, Natalia Ramos-Hernandez, Chris R. Riling, Erin A. Nowelsky and Paula M. Oliver, Nature Immunology 13(1): 77-85, 2012 PMCID: PMC3542978
The E3 ubiquitin ligase adaptor Ndfip1 regulates TH17 differentiation by limiting the production of pro-inflammatory cytokines
Ramon HE, Beal AM, Liu Y, Worthen GS, and Oliver PM, Journal Immunology 188(8): 4023-31, 2012 PMCID: PMC371391
Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells.
Yang B, Gay D, MacLeod MKL, Cao X, Hala T, Sweezer EM, Kappler J, Marrack P., Oliver PM, Nature Immunology 9(12): 1356-63, 2008 PMCID: PMC2935464