Novel regulatory mechanisms of nuclear factor (NF)-𝛋B signaling
MetadataShow full item record
Nuclear factor (NF)-𝛋B modulates the transcription of various target genes that are involved in innate and adaptive immune responses, and cell survival. The activation of NF-𝛋B is essential to protect cells from environmental stimuli and to properly direct cell development and differentiation. However, the aberrant activation of NF-𝛋B gives rise to human inflammatory and autoimmune diseases, including cancer. Therefore, there is a need to investigate the regulatory mechanisms of the NF-𝛋B pathways in order to improve therapeutic interventions. In this dissertation, I provide an evidence of a novel regulatory mechanism of noncanonical NF-𝛋B signaling by the inhibitor of apoptosis (IAP) binding motif (IBM) of NF-𝛋B-inducing kinase (NIK). I show that the NIK IBM causes NIK destabilization by promoting E3 ligase activity of c-IAP1 towards NIK, which ensures the suppression of noncanonical NF-𝛋B activation in the absence of an activating signal. In addition, I show that the NIK IBM specifically interacts with baculovirus IAP repeat (BIR) 2 of c-IAP1 in a competitive manner with the IBM of second mitochondrial activator of caspases (Smac), an IAP antagonist. Furthermore, I also examine the cleavage of CD30, a member of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF8), whose stimulation has been shown to activate canonical and noncanonical NF-𝛋B signaling. I demonstrate that TNFα-converting enzyme (TACE) proteolytically cleaves between alanine 373 and leucine 374 of CD30, in turn generating the CD30 fragment consisting of the transmembrane and intracellular domain (TM-ICD). I also show that CD30 TM-ICD is localized in both the cytoplasm and the nucleus, suggesting the need of further investigation with regard to the potential nuclear function of CD30 TM-ICD. Additionally, I demonstrate that CD30 produces CD30 TM-ICD constitutively in a ligand-independent manner in human anaplastic large cell lymphoma (ALCL) cells. Overall, this study reveals novel mechanistic insight into regulation of the NF-𝛋B pathways.