Paula M Oliver

faculty photo
Associate Professor of Pathology and Laboratory Medicine
Department: Pathology and Laboratory Medicine
Graduate Group Affiliations

Contact information
Cell Pathology Division 816F/ARC
Children’s Hospital of Philadelphia
The University of Pennsylvania
3615 Civic Center Blvd. 816F/ARC
Philadelphia, PA 19104
Office: 267-426-2839
Fax: 267-426-5165
BS (Zoology)
North Carolina State University, 1989.
PhD (Pathology)
University of North Carolina at Chapel Hill, 1998.
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Description of Research Expertise

Research Interest
Nedd4-family ubiquitylation networks that regulate T cell activation and effector differentiation.

Research Summary
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.

Lab Personnel

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)

Selected Publications

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.

Claire E. O’Leary, Emma L. Lewis, and Paula M. Oliver: Ubiquitylation as a rheostat for TCR signaling: from targeted approaches towards global profiling. Frontiers in Immunology 16(6): 618, Dec 2015.

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.

Vanessa Kurzweil, Ami Laroche, and Paula M. Oliver: Increased peripheral IL-4 leads to an expanded virtual memory CD8+ population. Journal of Immunology 20(5): 524-30, June 2014

Deshmukh H., Liu Y., Menkiti O., Mei J., Dai N., O’Leary C., Oliver P.M., Kolls J., Weiser J., and Worthen G.S.: The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nature Medicine 20(5): 524-30, May 2014.

Natalia Ramos-Hernández, Hilda E. Ramon, Allison M. Beal, Ami Laroche, Erin A. Dekleva and Paula M. Oliver: Ndfip1 enforces a requirement for CD28 co-stimulation by limiting IL-2 production. Journal of Immunology July (epub) 2013 PMCID: PMC3853121.

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.

Ramon HE, Beal AM, Liu Y, Worthen GS, and Oliver PM : The E3 ubiquitin ligase adaptor Ndfip1 regulates TH17 differentiation by limiting the production of pro-inflammatory cytokines. Journal Immunology 188(8): 4023-31, April 2012 PMCID: PMC371391.

Yang B, Gay D, MacLeod MKL, Cao X, Hala T, Sweezer EM, Kappler J, Marrack P., Oliver PM: Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells. Nature Immunology 9(12): 1356-63, December 2008 PMCID: PMC2935464.

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Last updated: 03/02/2017
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