TNFRSF1A - TNF receptor superfamily member 1A| Elisa - Clia - Antibody - Protein

Background

TNFRSF1A, also known as Tumor Necrosis Factor Receptor Superfamily Member 1A or TNFR1, is a prominent cell surface receptor that binds tumor necrosis factor-alpha (TNF-α). TNFR1 plays a critical role in regulating immune responses, cell survival, apoptosis, and inflammation, making it an essential component in both innate and adaptive immunity. The TNFRSF1A gene is located on chromosome 12p13.31 and encodes a protein that is expressed in nearly all cell types, with high expression in immune cells, epithelial cells, and neurons.

As a member of the TNF receptor superfamily, TNFRSF1A is involved in multiple signaling pathways, depending on cellular and environmental conditions. Upon binding to TNF-α, TNFR1 can trigger both pro-inflammatory responses and cell death pathways, depending on the context of signaling and additional molecules present. This receptor’s dual role is tightly regulated, as overactivation of TNFR1-mediated pathways can lead to pathological inflammation, while insufficient TNFR1 activity may hinder immune responses.

Protein Structure

TNFRSF1A (TNFR1) is a type I transmembrane protein with a modular structure comprising:

Extracellular Domain (ECD):

• The extracellular domain, which is approximately 180 amino acids in length, is responsible for ligand binding. This domain contains four cysteine-rich domains (CRDs), which are crucial for binding TNF-α with high affinity.
• These CRDs maintain the structure of the extracellular region and mediate trimerization, which is essential for initiating signaling pathways.
• The ligand-binding capability of the extracellular domain is facilitated by disulfide bridges within these cysteine-rich domains, ensuring structural integrity and correct receptor conformation for efficient TNF-α binding.

Transmembrane Domain (TMD):

• The transmembrane domain is a hydrophobic α-helix that anchors TNFR1 into the cell membrane. This domain enables the receptor to span the membrane, linking the extracellular and intracellular domains, and facilitates the transmission of conformational changes upon ligand binding.

Intracellular Domain (ICD):

• The intracellular domain of TNFR1 is the signaling hub that interacts with various adaptor proteins upon TNF-α binding. A crucial region within this domain is the death domain (DD), a conserved region responsible for recruiting downstream signaling molecules.
• This domain is essential for apoptosis signaling and NF-κB activation, as it serves as the docking site for several adapter proteins, such as TRADD (TNFRSF1A-associated death domain protein), which in turn recruits other signaling proteins.
• Phosphorylation of tyrosine residues within the intracellular domain further modulates its interaction with downstream effectors, diversifying the range of signaling pathways activated.

Classification and Subtypes

TNFRSF1A is classified within the TNF receptor superfamily due to its structural homology and functional properties shared with other TNF receptor members. Although TNFR1 (TNFRSF1A) does not have distinct subtypes, it works in close association with TNFRSF1B (TNFR2), another receptor for TNF-α. TNFR1 and TNFR2 have overlapping and complementary roles in TNF signaling. While TNFR1 is broadly expressed and mediates both pro-apoptotic and pro-inflammatory signaling, TNFR2 is primarily expressed on immune cells and predominantly mediates cell survival and immune regulation.

Function and Biological Significance

TNFRSF1A plays a key role in a variety of cellular and immune processes, primarily through its ability to bind TNF-α and activate multiple signaling cascades. The biological significance of TNFRSF1A includes:

Inflammatory Response Activation:

• Upon TNF-α binding, TNFR1 initiates the NF-κB pathway, leading to the transcription of pro-inflammatory genes, such as cytokines (e.g., IL-6 and IL-1β), chemokines, and adhesion molecules. This activation promotes immune cell recruitment and enhances inflammation at the site of infection or tissue damage.

Apoptosis and Cell Death:

• TNFR1 contains a death domain that enables it to activate caspase-dependent apoptotic pathways. In the presence of pro-apoptotic signals, TNFR1 recruits TRADD, FADD, and caspases to form a complex that initiates programmed cell death. This function is crucial in maintaining immune cell homeostasis and eliminating infected or damaged cells.

Cellular Survival and Repair:

• TNFR1 can also activate the MAPK (mitogen-activated protein kinase) pathway, which promotes cellular survival, repair, and proliferation. This response is often balanced with pro-apoptotic signals to maintain cell viability during immune responses.

Role in Adaptive Immunity:

• TNFR1 signaling influences adaptive immunity by modulating the activity of T cells and dendritic cells. The pro-inflammatory cytokines induced by TNFR1 help shape T cell differentiation, particularly towards Th1 responses, which are essential for fighting intracellular pathogens and malignancies.

Angiogenesis:

• TNFR1 activation can lead to angiogenic responses, primarily through the upregulation of pro-angiogenic factors like VEGF (vascular endothelial growth factor). This response plays a role in tissue repair and the pathological angiogenesis associated with cancer and chronic inflammation.

Tumor Surveillance and Immune Regulation:

• TNFR1 signaling is implicated in the immune response against tumor cells. By modulating inflammation and apoptosis, TNFR1 can influence tumor growth and immune-mediated tumor surveillance.

Clinical Issues

The dual role of TNFRSF1A in promoting cell survival and apoptosis can lead to various clinical conditions if dysregulated. Notably, TNFRSF1A dysfunction or overactivation is implicated in:

Autoimmune and Inflammatory Diseases:

• Overactivation of TNFR1 is associated with chronic inflammatory and autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), and psoriasis. The excessive TNFR1-mediated NF-κB activation leads to sustained inflammation and tissue damage.
• In some genetic disorders, mutations in the TNFRSF1A gene result in TNF receptor-associated periodic syndrome (TRAPS), an autoinflammatory condition characterized by recurrent fever, abdominal pain, myalgia, and skin rashes. TRAPS arises from missense mutations in TNFRSF1A that impair its ability to downregulate inflammatory responses.

Cancer:

• TNFR1 signaling plays a dual role in cancer progression. On one hand, it can induce apoptosis in cancer cells, while on the other, chronic TNF-α/TNFR1 signaling in the tumor microenvironment may contribute to tumor growth and metastasis by promoting inflammation, cell survival, and angiogenesis.
• Chronic inflammation associated with TNFR1 has been linked to various cancers, including colorectal cancer, hepatocellular carcinoma, and lung cancer.

Neurodegenerative Diseases:

• TNFR1 is also implicated in neurodegenerative diseases such as Alzheimer’s disease and multiple sclerosis (MS), where TNFR1-mediated inflammation contributes to neuronal damage and disease progression.

Infectious Diseases:

• TNFR1 is involved in immune responses against pathogens, and its dysregulation can impact susceptibility to infections. For example, TNFR1 activity is implicated in both protection against and the pathology of chronic infections like tuberculosis.

Summary

TNFRSF1A (TNFR1) is a central receptor within the TNF receptor superfamily that binds TNF-α and activates a wide range of immune responses. Structurally, TNFR1 consists of an extracellular ligand-binding domain, a transmembrane anchor, and an intracellular signaling domain containing a death domain. TNFR1 signaling is highly versatile, leading to either pro-inflammatory responses via the NF-κB pathway or apoptosis via the caspase cascade, depending on the cellular context and associated adaptor proteins.

The receptor’s role in immune response, apoptosis, and cellular survival renders it essential in both protective and pathological responses. Clinically, dysregulation of TNFR1 is associated with autoimmune diseases, inflammatory conditions, cancers, and neurodegenerative disorders. TNF receptor-associated periodic syndrome (TRAPS) is a notable genetic disorder linked to TNFRSF1A mutations, exemplifying how TNFR1 dysregulation can lead to recurrent inflammatory episodes and systemic symptoms.

TNFR1 remains a therapeutic target for conditions characterized by excessive inflammation, with TNF-α inhibitors (e.g., etanercept, infliximab) commonly used in clinical settings to mitigate TNFR1-mediated effects in autoimmune diseases. Understanding TNFR1 structure, function, and regulation thus continues to provide critical insights for therapeutic strategies in inflammatory and immune-mediated diseases.