TNF/TNFR superfamily

The TNF/TNFR superfamily consists of a system of currently > 40 identified ligand and receptor proteins, most of which are produced by cells of the immune system and which influence cell proliferation, cell survival, cell differentiation and apoptosis of various cell systems. The membrane-bound and/or soluble ligands of the TNF superfamily interact with one or more specific membrane-bound and/or soluble receptors, which form the corresponding TNF receptor superfamily.

TNF superfamily ligands: TNF superfamily ligands are predominantly transmembrane proteins. They are active as trimers. The extracellular protein configurations differ significantly from each other. This explains their receptor specificity. A soluble form of some of the membrane-bound ligands is released by proteolytic cleavage, usually by proteinases (mostly metalloproteinases). However, some TNF superfamily ligands are also formed as soluble proteins and only then form secondary membrane-anchored heterotrimeric complexes.

TNF superfamily receptors: The TNF-like receptors are type 2 transmembrane proteins, i.e. membrane-bound proteins with 1-6 cysteine-rich domain(s), by which they are characterized. Soluble forms of some of the receptors can be cleaved off (by various stimuli), which then neutralize the associated ligands. TNF receptors can be divided into three groups based on their intracellular sequences:

1. This group of receptors contains so-called death domains in their intracellular part. These molecules activate caspases, which ultimately leads to apoptosis (programmed cell death) of the cell.
2. The second group of receptors contains TNF receptor-associated factor (TRAF)-interacting motifs (TIMs) in their cytoplasmic domain. Their activation leads to the activation of various signal transduction pathways such as the NF-κB pathway.
3. This receptor group does not transmit signals, but competes with the signal-transducing receptors for the ligands and thus regulates their activity.

Selection of important members of the tumor necrosis factor receptor superfamily

• TNFRSF1A gene: encoded protein: tumor necrosis factor receptor 1 (CD120a) Ligand: TNF-
• TNFRgSF1B gene: encoded protein: tumor necrosis factor receptor 2 (CD120b) ligand: TNF-
• LTBR gene: encoded protein: lymphotoxin beta receptor(CD18); ligand: lymphotoxin beta
• FASLG gene: encoded protein: Fas receptor(CD95/Apo-1); ligand: FasL
• TNFRSF11A gene: encoded protein: RANK (CD 265); ligand: RANKL
• TNFRSF13B gene: encoded protein: TACI (IGAD2, CD267); ligand: APRIL, BAFF, CAMLG
• TNFRSF13C gene: encoded protein: BAFF receptor (CD268); ligand: BAFF receptor
• EDA2R gene: encoded protein: Ectodysplasin A2 receptor (XEDAR); ligand: