TNFRSF1A

Official Full Name

TNF receptor superfamily member 1A

Organism

Homo sapiens

GeneID

7132

Background

This gene encodes a member of the TNF receptor superfamily of proteins. The encoded receptor is found in membrane-bound and soluble forms that interact with membrane-bound and soluble forms, respectively, of its ligand, tumor necrosis factor alpha. Binding of membrane-bound tumor necrosis factor alpha to the membrane-bound receptor induces receptor trimerization and activation, which plays a role in cell survival, apoptosis, and inflammation. Proteolytic processing of the encoded receptor results in release of the soluble form of the receptor, which can interact with free tumor necrosis factor alpha to inhibit inflammation. Mutations in this gene underlie tumor necrosis factor receptor-associated periodic syndrome (TRAPS), characterized by fever, abdominal pain and other features. Mutations in this gene may also be associated with multiple sclerosis in human patients. [provided by RefSeq, Sep 2016]

Synonyms

FPF; p55; p60; TBP1; TNF-R; TNFAR; TNFR1; p55-R; CD120a; TNFR55; TNFR60; TNF-R-I; TNF-R55;

Bio Chemical Class

Cytokine receptor

Protein Sequence

MGLSTVPDLLLPLVLLELLVGIYPSGVIGLVPHLGDREKRDSVCPQGKYIHPQNNSICCTKCHKGTYLYNDCPGPGQDTDCRECESGSFTASENHLRHCLSCSKCRKEMGQVEISSCTVDRDTVCGCRKNQYRHYWSENLFQCFNCSLCLNGTVHLSCQEKQNTVCTCHAGFFLRENECVSCSNCKKSLECTKLCLPQIENVKGTEDSGTTVLLPLVIFFGLCLLSLLFIGLMYRYQRWKSKLYSIVCGKSTPEKEGELEGTTTKPLAPNPSFSPTPGFTPTLGFSPVPSSTFTSSSTYTPGDCPNFAAPRREVAPPYQGADPILATALASDPIPNPLQKWEDSAHKPQSLDTDDPATLYAVVENVPPLRWKEFVRRLGLSDHEIDRLELQNGRCLREAQYSMLATWRRRTPRREATLELLGRVLRDMDLLGCLEDIEEALCGPAALPPAPSLLR

Open

Disease

Acute respiratory distress syndrome, Acute/subacute hepatic failure, Alopecia, Brain cancer, Chronic obstructive pulmonary disease, Diabetes mellitus, Indeterminate colitis, Intrathoracic organs injury, Multiple sclerosis, Ovarian cancer, Rheumatoid arthritis, Ulcerative colitis

Approved Drug

Clinical Trial Drug

4 +

Discontinued Drug

1 +

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Detailed Information

The TNFRSF1A gene maps to human chromosome 12p13.31, comprises ten exons, and encodes tumor necrosis factor receptor 1 (TNFR1), also known as CD120a or p55. The primary transcript yields a single-pass transmembrane protein of approximately 455 amino acids. Structurally, TNFR1 contains an extracellular region composed of four cysteine-rich domains (CRD1–4), with CRD2–3 forming the principal TNF-α binding interface, a hydrophobic α-helical transmembrane segment, and an intracellular death domain (DD) that spans the C-terminal region and mediates apoptotic signaling. TNFR1 exists in both a membrane-bound form (mTNFR1) and a soluble form (sTNFR1); proteolytic shedding of the ectodomain by metalloproteases releases sTNFR1, which functions as a decoy to neutralize free TNF-α.

Figure 1. Domain architecture of TNFR1, TNFR2, Fn14 and their ligands. (Siegmund D, et al., 2023)

Expression and Receptor Activation

TNFR1 is widely expressed across nucleated cell types and is particularly abundant on immune cells, endothelial cells, and certain neuronal populations. Ligand engagement begins when trimeric TNF-α binds mTNFR1, driving receptor clustering and conformational changes that expose the intracellular DD and recruit adaptor proteins such as TRADD. This proximal complex can bifurcate into distinct signaling branches: one recruits FADD and procaspase-8 to form an apoptotic death-inducing signaling complex, and the other engages TRAF2/RIP1 to activate NF-κB-dependent transcription. Importantly, an N-terminal region (CRD1) functions as a pre-assembly domain that promotes ligand-independent receptor self-association; mutations in this region can disrupt normal receptor behavior and lead to aberrant signaling.

Biological Functions and Signal Integration

TNFR1 is a central regulator of the balance between cell survival, inflammation, and programmed cell death, and its signaling output is context dependent. Transient or low-level stimulation tends to favor NF-κB activation, inducing anti-apoptotic and pro-inflammatory gene programs and promoting cell survival and host defense. By contrast, persistent or high-amplitude stimulation—or engagement in particular subcellular compartments such as endosomes—favors assembly of death complexes and initiation of apoptosis. Post-translational modifications of RIP1 act as molecular switches that bias pathway choice, and spatial compartmentalization of TNFR1 signaling underlies the selective engagement of survival versus death responses. Furthermore, circulating sTNFR1 serves as an important buffer of TNF activity, limiting excessive inflammation under physiological conditions.

Genetic Variants and Disease Mechanisms

Germline mutations in TNFRSF1A cause TNF receptor–associated periodic syndrome (TRAPS), an autosomal-dominant autoinflammatory disorder. Pathogenic variants cluster in the extracellular CRD regions and produce disease through multiple, non-exclusive mechanisms: misfolding and endoplasmic reticulum retention of mutant receptor, activation of the unfolded protein response and mitochondrial stress, reduced shedding and lower circulating decoy receptor levels, and altered ligand-independent receptor activation. These molecular derangements provoke excessive innate immune activation, tissue inflammation, and in chronic cases, secondary complications such as amyloid deposition. TNFR1 polymorphisms have also been linked to susceptibility or modulation of other inflammatory and neurological conditions, consistent with the receptor's pleiotropic roles.

Clinical Presentation, Diagnosis, and Management

Clinically, TRAPS presents as recurrent, self-limited episodes of fever accompanied by migrating myalgia, serosal inflammation, and characteristic periorbital swelling; laboratory markers of systemic inflammation rise during flares. Diagnosis rests on the combination of compatible clinical phenotype, family history, and genetic testing covering the full coding region of TNFRSF1A, mindful that some patients with suggestive features may lack identifiable coding mutations. Therapeutically, management has shifted from nonspecific anti-inflammatory measures toward targeted biologic interventions aimed at interrupting key mediators of the inflammatory cascade. Anti-TNF receptor fusion proteins and TNF blockers can be effective in some patients, but IL-1 pathway antagonists have emerged as highly effective in refractory cases. Supportive strategies and careful long-term monitoring for complications such as amyloidosis remain important.

Research Challenges and Future Directions

Key challenges include untangling genotype–phenotype variability and defining why identical mutations produce divergent clinical severities across individuals. Elucidating the molecular determinants that govern receptor folding, shedding and subcellular routing will inform novel corrective approaches, and strategies that target mutant-specific mechanisms—chaperone enhancers, allele-selective silencing, or modulators of RIP1 post-translational state—are promising avenues. Improved disease models, including patient-derived cell systems and humanized mouse strains, together with integrated multi-omics profiling, are needed to map modifier genes and environmental triggers, to enable precision prognostication and to guide the design of mutation-directed therapies.

Reference

Siegmund D, Zaitseva O, Wajant H. Fn14 and TNFR2 as regulators of cytotoxic TNFR1 signaling. Front Cell Dev Biol. 2023 Nov 6;11:1267837.
Shi G, Hu Y. TNFR1 and TNFR2, Which Link NF-κB Activation, Drive Lung Cancer Progression, Cell Dedifferentiation, and Metastasis. Cancers (Basel). 2023 Aug 28;15(17):4299.

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