Kaltschmidt C , Greiner JFW , Kaltschmidt B .

	Graphical Abstract
	Figure 1 Schematic view of canonical and non-canoncial NF-κB signaling in mammals. In canonical signaling, NF-κB exists in two forms: a latent form complexed with IκB retained within the cytoplasm, and activated NF-κB without inhibitory subunits, binding to DNA in the nucleus. Various extracellular stimuli activate NF-κB, such as bacterial and viral products, inflammatory cytokines, reactive oxygen species, ultraviolet light, and even neurotransmitters. Intracellularly, a kinase complex (IKK, IκB kinase) is activated, in turn, resulting in phosphorylation and linear ubiquitination of the heterodimer-associated IκB. Rapid degradation of IκB through ubiquitin-mediated proteasomal degradation is followed by nuclear import of NF-κB and binding to target gene promoters such as IκB. Later, IκB can enter the nucleus and terminate the expression of NF-κB-target genes. In non-canonical signaling, binding of ligands to respective receptors such as BAFFR leads to NF-κB-inducing kinase (NIK)-mediated phosphorylation of IKK1, which in turn results in processing of p100 to p52 and enables the translocation of p52/RELB into the nucleus and the initiation of target gene transcription. Expression patterns in human single cells measured by RNA sequencing differed considerably. Whereas RELA has low cell type-specificity, c-REL is predominantly expressed in monocytes and keratinocytes and RELB in monocytes and glandular cells (The Human Protein Atlas, www.proteinatlas.org (accessed on 23 July 2021)).
	Figure 2 Schematic view of the fly Drosophila melanogaster’s development (in (A–C)), also shown in comparison to that of vertebrates such as the frog Xenopus laevis and humans (in (D)). A fertilized Drosophila egg (A) starts to divide and forms an embryo where the cytoplasm is shared between all nuclei (syncytium, (B)). At this stage of development, a dorsoventral gradient initiates the nuclear localization of Dorsal (Dl, blue), which is the fly homolog of vertebrate NF-κB. Dl is nuclear in the ventral region, as can be seen in the cross-section of the fly embryo depicted in (C). Nuclei without Dl are depicted in red, and a graded amount of nuclear Dorsal is depicted in shades of blue, with the maximal Dl concentration in dark blue. Extracellular regulators such as Decapentaplegic (Dpp) inhibit nuclear orsal, whereas Dpp is inhibited by its antagonist Sog (short gastrulation protein). Vertebrates do not have a ventral nerve cord but have a spinal cord; thus, it would not be entirely surprising if molecular regulators were also turned in their orientation from ventral to dorsal. BMP-4, a homolog of Dpp, is expressed in the ventral domain (D), whereas Chordin, a homolog of Sog, is expressed in the dorsal domain.

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