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Abstract

Tumour Necrosis Factor (TNF) signaling plays a critical role in regulating apoptosis, inflammation, and cellular homeostasis across species. In Drosophila melanogaster, the simplified TNF pathway—centered around the ligand Eiger and its receptors Wengen and Grindelwald—mirrors the core features of the more complex mammalian system, making it an ideal model for dissecting TNF receptor (TNFR) signaling mechanisms. This dissertation investigates the role of the Drosophila melanoma antigen gene (dMAGE), a homolog of the mammalian MAGE protein family, in TNFR signaling, with an emphasis on apoptosis and tumourigenesis. Using genetic manipulation in Drosophila, including loss-of-function and gain-of-function approaches, this study demonstrates that dMAGE is essential for Eiger-induced apoptotic signaling. Functional assays, including the small eye phenotype model, reveal that dMAGE acts within the TNFR-JNK signaling axis. Epistasis experiments show that dMAGE operates upstream of the kinase TAK1 and functionally interacts with TNFR-associated adaptor proteins and E2/E3 ubiquitin ligases, suggesting a role in modulating ubiquitination-dependent apoptotic signaling. This conclusion is further supported by in vivo ubiquitination assays, which identify dMAGE as a key enhancer of ubiquitin signaling upon TNFR activation. Additionally, dMAGE is critical for the elimination of epithelial tumour cells with compromised polarity, highlighting its role in tumour suppression. The findings establish dMAGE as a conserved modulator of TNF signaling, highlighting its evolutionary parallels with mammalian MAGE-D1 and Necdin. By uncovering the role of dMAGE in apoptosis and tumour suppression, this research enhances our understanding of TNF pathway regulation and proposes Drosophila as a valuable model for studying MAGE-TNFR interactions in health and disease.