Activation of receptors of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) by heteromeric ligands of the TNF superfam,ily (TNFSF)

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The ligands of the TNF superfamily (TNFSF), with exception of LTa, assemble into homotrimers and occur as type II transmembrane and as soluble molecules. Besides the well investigated homotrimeric symmetric TNFSF ligands, there are also a few asymmetric heterotrimeric TNFSF ligands. For example, LTa forms heteromers with LTß and we found in own unpublished previous work formation of heterotrimers between EDA-A1 and EDA-A2. The activation of receptors of the TNF receptor superfamily (TNFRSF) by homotrimeric ligands takes place in two steps. First, a ligand trimer interacts with three receptor molecules. The resulting ligand-receptor complexes are unable to robustly trigger apoptosis and classical NF-kappaB signaling. In fact, the latter needs secondary interaction of the initially formed trimeric ligand-receptor complexes. Membrane-bound homotrimeric TNFSF ligands regularly trigger this second step. In the case of soluble TNFSF ligands, however, secondary aggregation of ligand-receptor complexes is dependent on the receptor type considered. Most soluble TNFSF ligand-induced receptor trimers do not cluster spontaneously and thus fail to trigger full receptor activation. A few TNFRSF receptors with a strong intrinsic capacity to autoaggregate (e.g.TNFR1), however, secondarily aggregate in response to soluble ligand molecules and allow full receptor activation. Heterotrimeric TNFSF ligands are not able to recruit three identical TNFRSF receptor molecules but instead can potentially interact with two types of TNFRSF receptors. If only one receptor type is expressed, the heteromeric ligands only bind one or two receptor molecules. It is furthermore unclear whether heterotrimeric TNFSF ligands act as agonists, modifiers or antagonists of their corresponding homotrimeric counterparts. Against the background of the 2-step model of TNFRSF receptor activation, this raises the question how heterotrimeric ligand molecules act at the molecular and cellular level. We will therefore investigate the mode of action of heterotrimeric TNFSF ligands on the example of LTa2ßb, EDA-A1(EDA-A2)2 and (EDA-A1)2EDA-A2. EDA-A1 and EDA-A2 are unique in the TNFSF by having besides the characteristic TNF homology domain also a collagen domain which allows the formation of homo- and heteromeric EDA-A1/2 hexamers. We will therefore also analyze the activity of hexameric EDA-A1/2 variants of defined stoichiometry. The planed studies are not only important to understand the biology of LTa2, EDA-A1 and EDA-A2 and their receptors but could also provide general insights in the function of heteromeric TNFSF molecules. The latter could help to develop in a rational manner non-naturally occurring TNFSF ligand variants with novel, potentially therapeutically valuable properties, e.g. ligand trimers that bind only one or two receptor protomers or TNFRSF receptor-bispecific hexamers.