| TNF-R1, also known as TNFRSF1A or CD120a, is a ubiquitously expressed transmembrane receptor from the TNF receptor superfamily that primarily mediates TNF-α signaling to regulate inflammation, cell survival, and apoptosis in a wide range of cell types. TNF-R1 consists of an extracellular domain with four cysteine-rich subdomains, CRD1 to CRD4, where CRD1 to CRD3 function as A1/B2 modules and CRD4 contains A1/C2 modules that facilitate receptor clustering, followed by a transmembrane helix and a roughly 180-residue cytoplasmic tail featuring a death domain of about 70 residues with six alpha-helices forming a TRADD-binding interface via conserved motifs such as Asp245 and Arg347. Upon binding to trimeric TNF-α, pre-liganded receptor dimers or trimers cluster through CRD1 PLAD and CRD4, inducing conformational changes that expose the death domain for TRADD recruitment. This process initiates the formation of Complex I, composed of TRADD, RIP1, TRAF2, and cIAP1/2, which promotes K63 and K11-linked ubiquitination and activates the NF-κB/IKK pathway, driving pro-survival and inflammatory responses through RelA/p50, as well as MAPK and JNK signaling. Alternatively, when survival signals are insufficient, TNF-R1 can assemble Complex II, including TRADD, FADD, and caspase-8, to trigger extrinsic apoptosis. The core biological function of TNF-R1 is to balance immune defense, such as cytokine production and leukocyte recruitment, with the risk of immunopathology, while receptor endocytosis at low pH leads to complex dissociation and signal termination. TNF-R1 is relevant to autoimmunity, such as rheumatoid arthritis and inflammatory bowel disease. |
