Polymorphic Variants of LIGHT (TNF Superfamily-14) Alter Receptor Avidity and Bioavailability

Abstract

The TNF superfamily member homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes (LIGHT) [TNF superfamily (SF)-14], is a key cytokine that activates T cells and dendritic cells and is implicated as a mediator of inflammatory, metabolic, and malignant diseases. LIGHT engages the lymphotoxin-β receptor (LTβR) and HVEM (TNFRSF14), but is competitively limited in activating these receptors by soluble decoy receptor-3 (DcR3; TNFRSF6B). Two variants in the human LIGHT alter the protein at E214K (rs344560) in the receptor-binding domain and S32L (rs2291667) in the cytosolic domain; however, the functional impact of these polymorphisms is unknown. A neutralizing Ab failed to bind the LIGHT-214K variant, indicating this position as a part of the receptor-binding region. Relative to the predominant reference variant S32/E214, the other variants showed altered avidity with LTβR and less with HVEM. Heterotrimers of the LIGHT variants decreased binding avidity to DcR3 and minimized the inhibitory effect of DcR3 toward LTβR-induced activation of NF-κB. In patients with immune-mediated inflammatory diseases, such as rheumatoid arthritis, DcR3 protein levels were significantly elevated. Immunohistochemistry revealed synoviocytes as a significant source of DcR3 production, and DcR3 hyperexpression is controlled by posttranscriptional mechanisms. The increased potential for LTβR signaling, coupled with increased bioavailability due to lower DcR3 avidity, provides a mechanism of how polymorphic variants in LIGHT could contribute to the pathogenesis of inflammatory diseases.

Polymorphisms in Genes Encoding Metalloproteinase 9 and Lymphotoxin- Alpha can Influence Warfarin Treatment

“…The inflammatory cytokineTNFSF14, also known as LIGHT, is involved in cell survival and proliferation in the regulation of innate and adaptive immune response [22][23][24]. In this study, no association was found between polymorphisms in TNFSF14 and variability in weekly dose of warfarin.…”

Mechanistic Basis for Functional Promiscuity in the TNF and TNF Receptor Superfamilies: Structure of the LIGHT:DcR3 Assembly

“…DcR3 exists solely as a soluble molecule, obviating steric conflicts that might preclude formation of the interlocking assembly in vivo . Interestingly, a natural variant of LIGHT, E214K, which is close to the trans interaction interface (Figure S9), has been implicated in inflammatory diseases (Cheung et al, 2010). However, solution and cell-based studies failed to detect this higher order assembly and at present no direct experimental evidence exists supporting a physiological role for the interlocking dodecamer.…”

The TNF Receptor Superfamily in Co-stimulating and Co-inhibitory Responses

“…This network is controlled by an additional factor in primates, DcR3 ( TNFRSF6B ) that engages LIGHT, TL1A and FasL, binding with high affinity to LIGHT (Liu et al, 2014). DcR3 lacks a transmembrane domain yet localizes within tissues via a heparin binding site (Cheung et al, 2010b). A role for this regulator and its ligands in inflammation emerged with the identification of DcR3 (TNFRSF6B) deficiency in patients with early onset inflammatory bowel disease (Cardinale et al, 2013).…”