TNFRSF1A

TNFRSF1A, or tumor necrosis factor receptor superfamily member 1A, is a human gene that encodes the receptor TNF receptor 1 (TNFR1, also called p55). It is a member of the TNF receptor superfamily and is activated by tumor necrosis factor-alpha (TNF-α), as well as by transmembrane TNF. The receptor is widely expressed on many cell types, particularly immune cells, and mediates inflammatory and cell survival signals.

The protein is a type I transmembrane glycoprotein. Its extracellular region contains four cysteine-rich repeats that bind TNF, followed by a single transmembrane segment and a cytoplasmic death domain. This configuration enables TNFR1 signaling to propagate downstream pathways that regulate inflammation, cell survival, and cell death.

Upon TNF binding, TNFR1 trimerizes and recruits adaptor proteins such as TRADD, RIPK1, and TRAF2/5. This leads to activation of NF-κB and MAPK signaling, promoting inflammatory gene expression. Under specific conditions, TNFR1 signaling can also engage caspase-8 via FADD to induce apoptosis, or shift toward necroptotic pathways. Signaling outcomes are modulated by ubiquitination and the involvement of cIAPs.

Clinical significance of TNFRSF1A is most prominent in TNF receptor-associated periodic syndrome (TRAPS), an autoinflammatory disorder characterized by recurrent fevers, abdominal pain, myalgia, rash, and serositis. Many disease-causing mutations affect receptor processing or trafficking, contributing to ER stress and dysregulated signaling. Treatments include anti-TNF and IL-1–targeted therapies in select cases, together with genetic testing for diagnosis. The gene is located on chromosome 12 in humans. Interacting proteins include TRADD, RIPK1, TRAF2/5, FADD, and caspase-8.

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