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-beta receptor (LT beta R) 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 LT beta R and less with HVEM. Heterotrimers of the LIGHT variants decreased binding avidity to DcR3 and minimized the inhibitory effect of DcR3 toward LT beta R-induced activation of NF-kappa B. 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 LT beta R 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- journalArticle
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- Medicine and Health Sciences
- T-CELL-ACTIVATION
- LYMPHOTOXIN-BETA-RECEPTOR
- HERPESVIRUS ENTRY MEDIATOR
- SYSTEMIC-LUPUS-ERYTHEMATOSUS
- DECOY RECEPTOR-3
- HEPATOCELLULAR-CARCINOMA
- RHEUMATOID-ARTHRITIS
- EXPRESSION
- LYMPHOCYTE-ACTIVATION
- APOPTOSIS