TNFRrelated

TNFRrelated refers to the tumor necrosis factor receptor (TNFR) superfamily, a broad group of type I transmembrane receptors that bind TNF ligands to regulate immune responses, cell survival, development, and apoptosis. Members share extracellular cysteine-rich domains and diverse intracellular motifs that determine signaling outcomes. Ligand binding can initiate membrane-bound signaling or lead to the formation of soluble receptors (sTNFRs) through proteolytic shedding, which can act as decoys to dampen signaling.

Signaling through TNFRs is diverse and context dependent. TNFR1 (TNFRSF1A) contains a death domain and can activate both survival and death pathways. After TNF-α binding, adaptor proteins such as TRADD, RIPK1, and TRAF2 assemble, triggering NF-κB and JNK pathways that promote inflammation and cell survival; under certain conditions, caspase-8–mediated apoptosis can ensue. TNFR2 (TNFRSF1B) lacks a death domain and signals mainly through TRAF2 and NF-κB, supporting immune activation and regulatory T cell function. Cross-talk between receptors modulates the overall cellular response.

Biological roles of the TNFR family span immune regulation, lymphoid development, dendritic cell activation, B and T cell function, and bone remodeling via RANK–RANKL signaling. Related receptors contribute to neurotrophin signaling, including the p75 neurotrophin receptor (NGFR), which is considered part of the TNFR-related repertoire. The family also includes decoy and scavenger receptors (for example, DcR3 and osteoprotegerin) that tune ligand availability and signaling.

Clinical relevance remains high, as dysregulated TNFR signaling is linked to autoimmune and inflammatory diseases, infections, and cancer. Therapeutic approaches include TNF inhibitors and receptor-modulating agents that target TNF–TNFR signaling, reflecting ongoing research and clinical use in immune-mediated conditions.