Autophagy- and TBK1- mediated regulation of TRAF2/3 in alternative NF-κB signalling
Newman, Alice Clare
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Autophagy is a core cytoplasmic degradation process. It is established that KRas-mutant lung cancer cells require basal autophagy for survival. However, the mechanisms that govern this are poorly understood. It has recently been suggested that selective autophagic degradation of signalling complexes may regulate downstream cell signalling pathways. Primarily, this thesis aims to uncover molecular mechanisms through which selective autophagy can regulate signalling pathways that may impact upon cancer cell proliferation. Previous work in the lab identified a putative interaction between the signalling protein TRAF3 and the autophagy protein Ndp52 via mass spectrometric screening. In this thesis I have identified TRAF3 as a target of selective autophagy in both KRas-mutant lung cancer cells and in in vitro transformed MEFs. TRAF3 is a negative regulator of a gene expression regulation pathway called alternative NF-κB. As such, autophagy of TRAF3 promotes basal activation of the alternative NF-κB signalling pathway. This basal activity supports the proliferation of cancer cells. Investigation of TRAF2, a protein closely related to TRAF3, revealed that it too associates with the autophagy pathway, but is not degraded. This is promoted by the activity of TBK1, which itself can phosphorylate TRAF2. Both TBK1 and TRAF2 promote alternative NF-κB signalling, and I investigate possible mechanisms underlying this, including changes in TRAF3 mRNA and protein levels and binding to other alternative NF-κB regulators. This thesis therefore identifies mechanisms through which basal alternative NF-κB signalling is regulated in KRas-mutant lung cancer cells, with implications for cell proliferation. Ultimately, this work provides valuable mechanistic insight to inform the use of autophagy and/or TBK1 inhibition in future cancer therapies.