B cell activation is tightly regulated to ensure the specificity and efficacy of the antibody responses. Abnormalities in this regulation lead to immune deficiency and autoimmune diseases. Conversely, the efficacy of a vaccine depends on its ability to activate B cell responses. The long term goal, of this project is to delineate the cellular and molecular mechanism for the initiation and regulation of B cell activation. B cell activation is initiated by the binding of antigens to the B cell antigen receptor (BCR), which induces signaling cascades and antigen internalization for processing and presentation. The BCR is unique in that it recognizes antigens in their native forms and serves as a signaling transducer as well as an antigen transporter. The BCR coordinates its two functions to achieve an optimal level of activation. An early event in B cell activation is the association of the BCR with the actin cytoskeleton and the actin cytoskeleton reorganization. Recent studies show that the actin cytoskeleton is required for BCR-mediated antigen transport and is involved in regulating BCR signaling. However, the underlying mechanism by which the actin cytoskeleton regulates BCR functions has not been well studied. Mammalian actin-binding protein 1 (mAbp1/SH3P7/HP-55) that has been shown to simultaneously interact with F-actin and proteins of the other cellular systems is one of the potential linkers that bridge the interaction between the actin cytoskeleton and the BCR. The central hypothesis of this proposal is that in response to different antigens, the BCR differentially activates the mAbp1 and induces the interaction of mAbp1 with BCR signaling and antigen- transport machineries, which links the actin cytoskeleton with BCR signaling and antigen-transport apparatus. To test this hypothesis, we propose to define the roles of mAbp1 in the signaling and antigen- transport functions of the BCR, to examine BCR-triggered activation of mAbp1, and to analyze the interaction of mAbp1 with the components of BCR signaling and antigen-transport pathways. The proposed studies combine genetic, cell biological, and biochemical approaches and aim to identify novel functions of mAbp1 in B cell activation and delineate the molecular basis for the functional interaction between the BCR and the actin cytoskeleton. These studies will increase our understanding of underlying mechanisms for regulation of B cell activation and enhance our ability to manipulate and control antibody responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059617-04
Application #
7618533
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Ferguson, Stacy E
Project Start
2006-05-01
Project End
2012-04-30
Budget Start
2009-05-01
Budget End
2012-04-30
Support Year
4
Fiscal Year
2009
Total Cost
$247,544
Indirect Cost
Name
University of Maryland College Park
Department
Microbiology/Immun/Virology
Type
Schools of Earth Sciences/Natur
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742
Liu, Chaohong; Richard, Katharina; Wiggins, Melvin et al. (2016) CD23 can negatively regulate B-cell receptor signaling. Sci Rep 6:25629
Song, Wenxia; Liu, Chaohong; Upadhyaya, Arpita (2014) The pivotal position of the actin cytoskeleton in the initiation and regulation of B cell receptor activation. Biochim Biophys Acta 1838:569-78
Seeley-Fallen, Margaret K; Liu, Lisa J; Shapiro, Melanie R et al. (2014) Actin-binding protein 1 links B-cell antigen receptors to negative signaling pathways. Proc Natl Acad Sci U S A 111:9881-6
Song, Wenxia; Liu, Chaohong; Seeley-Fallen, Margaret K et al. (2013) Actin-mediated feedback loops in B-cell receptor signaling. Immunol Rev 256:177-89
Arunkumar, Nandini; Liu, Chaohong; Hang, Haiying et al. (2013) Toll-like receptor agonists induce apoptosis in mouse B-cell lymphoma cells by altering NF-?B activation. Cell Mol Immunol 10:360-72
Liu, Chaohong; Bai, Xiaoming; Wu, Junfeng et al. (2013) N-wasp is essential for the negative regulation of B cell receptor signaling. PLoS Biol 11:e1001704
Liu, Chaohong; Fallen, Margaret K; Miller, Heather et al. (2013) The actin cytoskeleton coordinates the signal transduction and antigen processing functions of the B cell antigen receptor. Front Biol (Beijing) 8:475-485
Liu, Chaohong; Miller, Heather; Sharma, Shruti et al. (2012) Analyzing actin dynamics during the activation of the B cell receptor in live B cells. Biochem Biophys Res Commun 427:202-6
Liu, Chaohong; Miller, Heather; Orlowski, Gregory et al. (2012) Actin reorganization is required for the formation of polarized B cell receptor signalosomes in response to both soluble and membrane-associated antigens. J Immunol 188:3237-46
Liu, Chaohong; Miller, Heather; Hui, King Lam et al. (2011) A balance of Bruton's tyrosine kinase and SHIP activation regulates B cell receptor cluster formation by controlling actin remodeling. J Immunol 187:230-9

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