Date of Degree
PhD (Doctor of Philosophy)
Gail A. Bishop
Tumor-necrosis factor (TNF)-receptor (R) associated factor 3 (TRAF3) is an important adaptor protein that plays a variety of context-dependent regulatory roles in all types of immune cells. In B cells, TRAF3 mediates signaling downstream of CD40, B cell activating factor (BAFF)-R, and toll-like receptors (TLR)s to restrain B cell survival and function. Downstream of CD40 and BAFF-R, TRAF3 negatively regulates NF-κB2 activation through NF-κB inducing kinase (NIK) stabilization. NF-κB2 activation is important for B cell-homeostatic survival. However, the constitutively active NF-κB2 in other TRAF3 deficient immune cell types does not lead to increased cell survival. More importantly, loss-of-function mutations of the TRAF3 gene are found at relatively high frequencies in B cell malignancies such as multiple myeloma and B cell lymphoma. Therefore, TRAF3 plays a critical and unique role in B cells to restrain cell survival and differentiation that contributes to B cell malignancies. In this study, we aim to identify TRAF3 modulated survival pathways that contribute to homeostatic B-cell survival and B-cell differentiation.
We found that TRAF3 degradation was not sufficient or necessary to induce NF-κB2 activation. We also showed that TRAF3 degradation is dependent on association with TRAF2 and cytoplasmic tail of CD40 or BAFF-R. TRAF3 regulation of NIK is important for mature B cell development; however, NIK only partially contributes to TRAF3-mediated B cell survival. TRAF3 also regulates the protein level of proviral integrations of Moloney virus (Pim2), a pro-survival serine/threonine protein kinase encoded by the Pim2 gene, to restrain B cell survival; this regulation can operate independently of the NF-κB2 pathway. Furthermore, we showed that TRAF3 negatively regulates IL-6R signaling, a pathway that contributes to expansion of the plasma cell compartment and to the pathogenesis of multiple myeloma, a plasma cell malignancy. We found that TRAF3 facilitates recruitment of PTPN22, a tyrosine phosphatase, to associate with Jak1 following IL-6 binding to the IL-6R complex. This regulation by TRAF3 restrains plasma cell differentiation, and also provides the first demonstration that PTPN22 regulates cytokine receptor signaling.
Collectively, these findings highlight the importance of TRAF3 in the regulation of B cell-specific survival and differentiation pathways. This information could be exploited for more precise and effective therapeutic choices in treatment of B cell malignancies with TRAF3 deficiencies.
Tumor-necrosis factor (TNF)-receptor (R) associated factor 3 (TRAF3) is a protein that is often found to have become non-functional in blood cell cancers that arise from a type of white blood cell called B lymphocytes. B lymphocytes are cells in our immune system that help fight off infections by producing antibodies. One way TRAF3 normally prevents B-cell cancers such as multiple myeloma and lymphoma is by controlling normal B cell survival. Without TRAF3, B cells survive too long, allowing them to accumulate abnormal genetic changes (mutations) that lead to cancerous growth. A major goal of my dissertation research was to determine how TRAF3 regulates B cell survival. I discovered that multiple distinct proteins are regulated by TRAF3, and showed molecular details by which TRAF3 regulates these proteins, and how in turn each of the proteins impacts B cell survival. A currently popular theory proposed that only a single pathway that signals to B cells accounts for all of the effects of TRAF3, but my work showed that this is not the case. Rather, this pathway accounts for only part of TRAF3’s functions, and I identified additional survival factors regulated by TRAF3. Additionally, my work shows that TRAF3 controls the process by which a B cell becomes an antibody-secreting cell, called a plasma cell. This is also relevant to human B cell cancers, because the tumor multiple myeloma is derived from plasma cells. My work demonstrated that TRAF3 restrains signaling to B cells by a specific receptor that determines plasma cell development.
The impact of the work presented in this dissertation is the identification of the events and pathways that are abnormal when TRAF3 sustains mutations that impair its function, such as mutations found in B cell cancers. This information can be used for better and more precise selection of effective treatments for B cell cancer.
publicabstract, B cell, IL-6, NIK, PTPN22, TRAF3
xii, 124 pages
Includes bibliographical references (pages 108-124).
Copyright 2015 Wai Wai Lin