Paula M. Oliver, Ph.D.
Assistant Professor, Dept of Pathology and Laboratory Medicine

Microbioloby, Virology, and Parasitology Program

Abramson Research Center (ARC) 816F
Philadelphia, PA 19104-6069

Office tel.: 267 427-2839
Lab tel.: 267 427-0292
Fax: 267 426-5165
E-mail: paulao@mail.med.upenn.edu

Education

North Carolina State University: BS (Zoology), 1989.

UNC-Chapel Hill: PhD (Pathology), 1998.

National Jewish Medical and Research Center: Postdoctoral Research.

Research Interests

• Regulation of infection and the adaptive immune response by members of the Nedd4-family.
• Regulation of ubiquitination by Nedd4-family interacting proteins (Ndfip1 and Ndfip2).

Key words: Autoimmune disease; immunodeficiency; lysosomal degradation; proteasomal degradation; Nedd4-family; E3 ubiquitin ligase.

Description of Research

T cells play a central role in orchestrating the immune response to pathogen infection. To do this, T cells respond to infection by proliferating and differentiating into diverse effector subsets. Through this transition, T cells must continually adjust their levels of key regulatory proteins. To alter protein levels, T cells must alter protein synthesis or change the rate of protein degradation. 'Tagging' a protein with ubiquitin can cause its degradation. Thus, ubiquitin-mediated degradation is an important process in regulating the fate of an activated T cell.

My laboratory studies the ubiquitination pathways regulated by the Nedd4-family of E3 ubiquitin ligases. We are particularly interested in how these pathways alter T cell responsiveness and change the course of pathogen infection. In addition, we are investigating in how dysregulation of ubiquitin-mediated pathways impacts T cell mediated diseases such as autoimmunity and acquired immunodeficiency.

1. Several members of the Nedd4-family are expressed in T cells and are known to regulate T cell activation. Two of these ligases, Nedd4-1 and Itch, while quite similar in structure, affect T cell function quite differently. Itch destroys proteins that promote T cell activation, and thus dampens the immune response. On the contrary, we have found that Nedd4-1 removes inhibitory proteins and thus promotes the immune response. It does this, in part, by causing the destruction of Cbl-b. We hypothesize that Nedd4-1 cooperates with endosomal and multi-vessicular body proteins to promote Cbl-b degradation. Supporting this, we recently identified several proteins involved in endosomal/lysosomal sorting pathways that physically interact with Nedd4-1. We are now characterizing these interactions in more detail and trying to determine whether Cbl-b is degraded via a ubiquitin-dependent endosomal/lysosomal mediated mechanism. In the future we would like to define Nedd4-family ubiquitination pathways in T cells. To do this we will identify targets and characterize how Nedd4-family members are regulated, whether by phosphorylation or by other mechanisms.


2. Nedd4-family members associate with membrane tethered interacting proteins such as Ndfip1 and Ndfip2. We hypothesize that these interacting proteins regulate members of the Nedd4 family. There are several lines of evidence supporting this. First, we recently showed that Ndfip1 binds Itch in T cells and promotes Itch ubiquitination of target proteins. Second, in the absence of Ndfip1, while Itch is expressed, its targets are not degraded. This helps to explain why mice lacking Ndfip1 resemble Itch deficient mice. Both Itch deficient mice and Ndfip1 deficient mice develop an inflammatory disease characterized by skin lesions that resemble the human condition known as atopic dermatitis. While our data show that Ndfip1 regulates Itch, we believe that Ndfip1 also regulates other Nedd4-family members. Additionally, we believe that all Nedd4-family members are regulated through their association with various types of interacting proteins. We are currently trying to determine how these interacting proteins regulate protein ubiquitination and attempting to identify functional E3 Ub ligase/interacting protein pairs that are regulate T cell function in vivo.

Recent Publications

Oliver PM, Yang B, MacLeod MLK, Cao X, Sweezer, EM, Hala, T, Kappler J, Marrack P. Nedd4-1 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells. Under revision.

Oliver PM, Cao X, Worthen GS, Peijun S, Briones N, MacLeod M, White J, Kirby P, Kappler J, Marrack P, Yang B. (2006) Ndfip1 protein promotes the function of Itch ubiquitin ligase to prevent T cell activation and T helper 2 cell-mediated inflammation. Immunity Dec;25(6) 25, 929-40.

Oliver PM, Vass T, Kappler J, Marrack P. (2006) Loss of the proapoptotic protein, Bim, breaks B cell anergy. J Exp Med. March 6, 203(3) 731-41..

Oliver PM, Wang M, Zhu Y, White J, Kappler J, Marrack P. (2004) Loss of Bim allows precursor B cell survival but not precursor B cell differentiation in the absence of interleukin 7. J Exp Med. Nov 1;200(9):1179-87.

Search PubMed for more articles

Lab

Rotation Projects

1. Role of Nedd4-1 in CD8+ CTL differentiation and function
2. Role of phosphorylation in Nedd4-1 ubiquitin ligase function
3. Identifying Nedd4-1 family members regulated by Ndfip1.

Lab Personnel

Denise Gay, PhD
Tamara Hala, Technical support