Receptor Oligomerization and Its Relevance for Signaling by Receptors of the Tumor Necrosis Factor Receptor Superfamily

Abstract

With the exception of a few signaling incompetent decoy receptors, the receptors of the tumor necrosis factor receptor superfamily (TNFRSF) are signaling competent and engage in signaling pathways resulting in inflammation, proliferation, differentiation, and cell migration and also in cell death induction. TNFRSF receptors (TNFRs) become activated by ligands of the TNF superfamily (TNFSF). TNFSF ligands (TNFLs) occur as trimeric type II transmembrane proteins but often also as soluble ligand trimers released from the membrane-bound form by proteolysis. The signaling competent TNFRs are efficiently activated by the membrane-bound TNFLs. The latter recruit three TNFR molecules, but there is growing evidence that this is not sufficient to trigger all aspects of TNFR signaling; rather, the formed trimeric TNFL-TNFR complexes have to cluster secondarily in the cell-to-cell contact zone for full TNFR activation. With respect to their response to soluble ligand trimers, the signaling competent TNFRs can be subdivided into two groups. TNFRs of one group, designated as category I TNFRs, are robustly activated by soluble ligand trimers. The receptors of a second group (category II TNFRs), however, failed to become properly activated by soluble ligand trimers despite high affinity binding. The limited responsiveness of category II TNFRs to soluble TNFLs can be overcome by physical linkage of two or more soluble ligand trimers or, alternatively, by anchoring the soluble ligand molecules to the cell surface or extracellular matrix. This suggests that category II TNFRs have a limited ability to promote clustering of trimeric TNFL-TNFR complexes outside the context of cell-cell contacts. In this review, we will focus on three aspects on the relevance of receptor oligomerization for TNFR signaling: (i) the structural factors which promote clustering of free and liganded TNFRs, (ii) the signaling pathway specificity of the receptor oligomerization requirement, and (iii) the consequences for the design and development of TNFR agonists.

Keywords: NFκB; TNF ligand superfamily; TNF receptor (TNFR) family; cell death; receptor cluster.

FIGURE 1

Plasma membrane-associated expression results in high local TNFR concentrations in the TNFR-accessible shell (L_edR) around the cell resulting in dimer formation in the absence of ligand despite low auto-affinity (KD_P). Ligand trimers preferentially bind with higher affinity to dimeric (KD_RD) than to monomeric receptor (KD_RM) species. Liganded TNFR dimers are more stable than ligand-free TNFR dimers and are thus removed from the equilibrium with the monomers. Le Chatelier’s principle promotes then the net formation of new ligand-free receptor dimers. R_C, radius of the cell; V_RS, volume of the receptor accessible shell.

FIGURE 2

Clustering of TNFRs by membrane-bound and soluble TNFLs. For details, see text.

FIGURE 3

Scheme of TRAF2-interacting TNFR-induced activation of the classical NFκB pathway. For details, see text.

FIGURE 4

Scheme of CD95-induced caspase-8 activation. For details, see text.

FIGURE 5

Scheme of sTWEAK-induced activation of the alternative NFκB pathway. In non-stimulated cells, cytosolic TRAF2 and the cIAPs are engaged in NIK degradation, thus in suppression of the alternative NFκB pathway (left panel). Recruitment of TRAF2 and cIAPs to Fn14, irrespective whether triggered by soluble TWEAK or membrane TWEAK, results in reduced cytosolic TRAF2 and cIAP levels and thus reduced suppression of NIK degradation resulting in the activation of the alternative NFκB pathway by accumulated constitutively active NIK.

FIGURE 6

Clustering and activation of TNFRs by antibodies (aTNFRs). Antibodies bind with medium to high affinity to FcγRs (KD_F) and also with affinity to TNFRs (KD_a). The FcγR-bound aTNFRs act then like memTNFLs. Protein A binds multiple aTNFR molecules with high affinity (KD_PA). The resulting complexes act then as oligomeric sTNFLs.