NF-KappaB plays a pivotal role in the activation of T lymphocytes during immune responses. Upon engagement of T cell receptor (TCR) with a foreign antigen, a signal transduction cascade is activated, culminating in the activation of NFKB, which controls the expression of genes essential for the proliferation and function of T cells. While much is known about the pathways of NF-KB activation by proinflammatory cytokines, the mechanism by which NF-kappaB is activated by TCR is not well understood. A key regulator of NF-KappaB pathway is the IKappaB kinase (IKK) complex, which phosphorylates the NF-kappaB inhibitor IKappaB and targets this inhibitor for degradation by the ubiquitin-proteasome pathway, thus allowing NF-KappaB to enter the nucleus to control gene expression. BCL10, a CARD domain protein implicated in MALT lymphoma, has recently been shown to play an essential role in IKK activation by TCR in T lymphocytes. However, BCLI0 does not activate IKK directly, leaving a large gap in our understanding of the signaling pathways downstream of TCR. The major goal of this proposal is to understand how BCL10 is linked to IKK on the one hand, and to TCR on the other hand. In an effort to understand how BCL10 activates IKK, we have established a cell free system that activates IKK in response to addition of BCL10 protein. Fractionation of cell extracts led to the identification of several proteins operationally defined as IKABs (IKK Activators downstream of BCL10) that mediate IKK activation by BCL10 in vitro. Significantly, we find that IKK in T cells is activated by BCL10 through a ubiquitin-dependent but proteasome-independent mechanism. These results suggest that ubiquitination plays a regulatory role not only in innate immunity, but also in adaptive immunity. Our next step is to determine whether and how IKABs are involved in IKK activation in T lymphocytes (Aim 1). We will also investigate the mechanisms by which BCL10 activates IKABs (Aim 2). Finally, we will study how BCL10 is regulated by upstream signaling molecules in the TCR pathway (Aim 3). Collectively, these lines of investigation should lead to a better understanding of the NF-KappaB signaling pathways in T cells. Such knowledge is crucial to understanding and treating various human diseases, including MALT lymphoma and other immune disorders.
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