Three is better than one: pre-ligand receptor assembly in the regulation of TNF receptor signaling

Abstract

The tumor necrosis factor (TNF) family of cytokines and their receptors regulates many areas of metazoan biology. Specifically, this cytokine-receptor family plays crucial roles in regulating myriad aspects of immune development and functions. Disruption of ligand-receptor interaction or downstream signal transduction components in the TNF family often leads to pathological conditions. Historically, members of the TNF receptor family (TNFRs) were thought to exist as monomeric receptor chains prior to stimulation. Binding of the trimeric ligand then induces the trimerization of the receptors and activation of downstream signaling. However, recent evidence indicates that many TNFRs exist as pre-assembled oligomers on the cell surface. Pre-ligand assembly of TNFR oligomers is mediated by the pre-ligand assembly domain (PLAD), which resides within the membrane distal cysteine-rich domain of the receptors. Growing evidence indicates that PLAD-mediated receptor association regulates cellular responses to TNF-like cytokines, especially in cells of the immune system. Thus, targeting pre-ligand assembly may offer new possibilities for therapeutic intervention in different pathological conditions involving TNF-like cytokines.

Fig. 1

Schematic diagram of the structures of the three different subclasses of TNFRs. (A) The death receptors are characterized by the DDs in the signaling cytoplasmic tails. (B) The majority of TNFRs signal through binding to one of six TRAFs. (C) The decoy receptors lack intact cytoplasmic signaling tails and can exist as either soluble or membrane-bound forms. The blue ovals represent the cysteine-rich domains (CRDs). Receptors with four CRDs are shown for illustration purpose only. TNFRs can have one to six CRDs.

Fig. 2

The pre-ligand assembly model. (A) Upon ligand binding, the PLAD interaction is replaced by the more stable ligand-receptor interaction. A pre-assembled trimer is shown for illustration purpose. (B) Aggregation of pre-assembled dimers maintains the three-fold symmetry of the ligand-bound receptor complex. The receptor dimers are represented by the blue hexagons from a top-down view. Upon ligand binding, ligand-receptor aggregates formed on the membrane maintains a trimeric symmetry, as shown by the circle.

Fig. 3

(A) Regulation of FasL-induced apoptosis in CD4⁺ T-cells. Naïve or activated T-cells are relatively resistant to FasL because the majority of Fas are monomeric. TCR restimulation redistributes Fas to the lipid rafts, facilitates pre-ligand assembly and upregulates expression of FasL. This results in enhanced FasL-induced apoptosis. This process may mimic elimination of autoreactive T-cells that are repeatedly stimulated with autoantigens. (B) CD8⁺ T-cells are resistant to TRAIL-induced apoptosis due to pre-assembled TRAIL-R2 (blue) and TRAIL-R4 (brown) complexes. They are protected from TRAIL-induced apoptosis when restimulated through their TCR. This mimics the state of CD8⁺ T-cells that have received CD4⁺ T-cell help. However, if CD8⁺ T-cells receive no CD4⁺ T-cell help during initial priming (partial activation), the TRAIL-R2/TRAIL-R4 complex dissociates. These cells succumb to TRAIL-induced apoptosis upon restimulation of the TCR. This then results in failed memory CD8⁺ T-cell proliferation.