The Conserved Network of NF-κB Transcriptional Partners From Drosophila to Mammals

The nuclear factor κB (NF-κB) pathway governs innate immunity, orchestrating rapid transcriptional responses to infection. While the pathway is often depicted as a linear signaling cascade, NF-κB functions within a complex network of cooperative partnerships with other transcription factors and co-regulators. Here, current data about these NF-κB-centered transcriptional partnerships are described with a focus on the model organism Drosophila melanogaster and a comparative analysis with homologous mammalian factors. We detail how Drosophila melanogaster NF-κB factors (Relish, Dif, and Dorsal) cooperate with each other and other transcription regulators, such as Charon, PARP-1, Akirin, SWI/SNF, Mediator, Stat92E, AP-1, FOXO, Nubbin, Caudal, DEAF1, and GATA family transcription factors, to precisely shape immune specificity and homeostasis. We explore the evolutionary conservation of these mechanisms in mammals, where homologous factors similarly shape NF-κB activity to control inflammatory and antiviral responses. While the core principle of NF-κB cooperativity is ancient, the network has expanded and diversified in mammals, reflecting increased genomic and regulatory complexity. This comparative perspective underscores that the functions of NF-κB are fundamentally defined by its context-dependent partnership network.