The major focus of our research is understanding the signals which regulate B lymphocyte activation. We have a special interest in signals delivered to B cells through their interactions with T lymphocytes, and in recent years have particularly focused upon B cell signaling via CD40. Our recent findings have impressed upon us the potential importance of physical interactions between CD40 and cytoplasmic signaling proteins in cholesterol-rich membrane microdomains, or rafts. It was found the engagement of CD40 on B lymphocytes leads to the rapid recruitment to the CD40 cytoplasmic domain of tumor necrosis factor associated factors (TRAFs) 2 and 3. Both CD40 and TRAFs 2 and 3 become associated with detergent-insoluble, cholesterol-enriched membrane microdomains, or rafts, and the raft-recruited TRAFs become posttranslationally modified, with the appearance of multiple higher MW forms. This is followed by initiation of proteasome-dependent degradation of these two TRAFs. The central hypothesis underlying the proposed studies is that physical compartmentalization in the plasma membrane serves to regulate the interactions between CD40 and the TRAFs, to orchestrate CD40 signaling pathways. It is also proposed that effects on membrane compartmentalization play an important role in interactions between receptors and signaling proteins, as well as in interactions between individual receptors, determining the ultimate outcome of the message delivered to the B cell. Our specific experimental goals are (1) To determine how interactions between CD40 and TRAFs 2 and 3 in membrane microdomains regulate CD40 signaling, by investigating the nature of the CD40-induced modification of raft-recruited TRAF2 and TRAF3, how this modification is regulated and what role it plays in CD40 signaling, and identifying the protein-protein associations mediating initiation of the CD40 signaling cascade in membrane microdomains; (2) To investigate the nature of the interactions between CD40 and TRAFs 1 and 6 which are quite distinct from those between CD40 and TRAFs 2 and 3, and determining their roles in CD40 effector functions; and (3) To investigate how physical compartmentalization in the plasma membrane regulates the interaction between signaling by CD40, the B cell antigen receptor, and Fas.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049993-03
Application #
6632477
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Mallia, Conrad M
Project Start
2001-09-01
Project End
2005-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
3
Fiscal Year
2003
Total Cost
$294,000
Indirect Cost
Name
University of Iowa
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Jellusova, Julia; Miletic, Ana V; Cato, Matthew H et al. (2013) Context-specific BAFF-R signaling by the NF-?B and PI3K pathways. Cell Rep 5:1022-35
Hildebrand, Joanne M; Yi, Zuoan; Buchta, Claire M et al. (2011) Roles of tumor necrosis factor receptor associated factor 3 (TRAF3) and TRAF5 in immune cell functions. Immunol Rev 244:55-74
Tseng, Wendy; Lu, Jinxiu; Bishop, Gail A et al. (2010) Regulation of interleukin-6 expression in osteoblasts by oxidized phospholipids. J Lipid Res 51:1010-6
Hildebrand, Joanne M; Luo, Zhenghua; Manske, Michelle K et al. (2010) A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling. J Exp Med 207:2569-79
Peters, Anna L; Bishop, Gail A (2010) Differential TRAF3 utilization by a variant human CD40 receptor with enhanced signaling. J Immunol 185:6555-62
Peters, Anna L; Stunz, Laura L; Meyerholz, David K et al. (2010) Latent membrane protein 1, the EBV-encoded oncogenic mimic of CD40, accelerates autoimmunity in B6.Sle1 mice. J Immunol 185:4053-62
Kraus, Zachary J; Nakano, Hiroyasu; Bishop, Gail A (2009) TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40. Proc Natl Acad Sci U S A 106:17140-5
Poovassery, Jayakumar S; Vanden Bush, Tony J; Bishop, Gail A (2009) Antigen receptor signals rescue B cells from TLR tolerance. J Immunol 183:2974-83
Graham, John P; Moore, Carissa R; Bishop, Gail A (2009) Roles of the TRAF2/3 binding site in differential B cell signaling by CD40 and its viral oncogenic mimic, LMP1. J Immunol 183:2966-73
Peters, Anna L; Stunz, Laura L; Bishop, Gail A (2009) CD40 and autoimmunity: the dark side of a great activator. Semin Immunol 21:293-300

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