TNFRSF21 - TNF receptor superfamily member 21 |Elisa - Clia - Antibody - Protein

Background

TNF receptor superfamily member 21 (TNFRSF21), also known as death receptor 6 (DR6), is a member of the tumor necrosis factor receptor (TNFR) superfamily. Like other TNFR members, TNFRSF21 is involved in processes that modulate immune responses, cell death, and survival pathways. This receptor is particularly involved in apoptosis, immune cell regulation, and central nervous system functions. TNFRSF21/DR6 is expressed in a range of tissues but is predominantly found in lymphoid organs, nervous system cells, and tissues associated with inflammatory processes.

TNFRSF21 plays a significant role in neuroinflammation and neurodegeneration, as well as in the regulation of immune responses. It is a type I transmembrane protein that acts as a receptor for ligands like tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and amyloid precursor protein (APP)-derived peptides. Due to its involvement in cell apoptosis, particularly in neural cells, TNFRSF21 has garnered interest for its potential therapeutic applications in neurodegenerative diseases such as Alzheimer’s disease. Additionally, its function in immune cell regulation places it as a candidate target in autoimmune diseases and certain cancers.

Protein Structure

TNFRSF21/DR6 is a type I transmembrane glycoprotein composed of approximately 655 amino acids, with several distinct structural regions:

Extracellular Domain:

• The extracellular region consists of four cysteine-rich domains (CRDs) that are characteristic of the TNFR superfamily. These CRDs are necessary for ligand binding and receptor stability. Each CRD features a conserved cysteine pattern that stabilizes the protein through disulfide bond formation, creating a rigid, loop-like structure.
• The CRDs provide TNFRSF21 with a three-dimensional framework that allows it to interact with ligands such as TRAIL and APP. Structural studies indicate that each CRD contributes to ligand recognition, though the specific binding mechanism varies depending on the ligand.

Transmembrane Domain:

• TNFRSF21 has a hydrophobic transmembrane domain, responsible for anchoring the receptor within the cellular membrane. This domain is essential for TNFRSF21’s function as a membrane-bound receptor and allows it to interact with other membrane components and signaling molecules.

Intracellular Death Domain:

• The intracellular region of TNFRSF21/DR6 contains a well-conserved death domain (DD), which is critical for initiating downstream apoptotic signaling. The death domain mediates protein-protein interactions with adaptor molecules such as Fas-associated death domain (FADD) and TNFR-associated death domain (TRADD), which activate caspases and lead to programmed cell death.
• The DD is a region of around 80 residues that forms a six-helical bundle structure, essential for signal transduction related to apoptosis. The formation of death domain complexes triggers activation of downstream caspases, particularly caspase-8, which further amplifies apoptotic signaling.

Classification and Subtypes

TNFRSF21/DR6 belongs to the broader TNFR superfamily, which includes various receptors that play roles in immune response modulation, cell survival, apoptosis, and inflammation. Within the TNFR superfamily, TNFRSF21 is categorized as a “death receptor” due to its death domain, which confers pro-apoptotic capabilities. Other receptors in this subgroup include TNFR1, Fas/CD95, and TRAIL receptors.

Although TNFRSF21 itself does not have distinct isoforms or subtypes, its functional complexity arises from its interactions with various ligands, adaptors, and intracellular signaling molecules. The TNFRSF21 gene expression can be regulated by cellular context and inflammatory stimuli, affecting the receptor's functional roles across different tissues.

Function and Biological Significance

TNFRSF21/DR6 plays multifaceted roles, from mediating cell death to modulating immune responses and neurodevelopment. Key functional aspects include:

Apoptosis and Cell Death:

• TNFRSF21’s primary function in many cell types is to mediate apoptosis. Upon ligand binding, TNFRSF21’s death domain recruits adaptors like FADD and TRADD, which subsequently activate caspase-8. This caspase cascade culminates in programmed cell death.
• Apoptosis mediated by TNFRSF21 is crucial for regulating cell populations in both the immune system and nervous system. In the immune system, it ensures that over-activated or autoreactive T cells undergo apoptosis, maintaining immune homeostasis.

Immune Cell Regulation:

• TNFRSF21/DR6 is highly expressed in immune cells, particularly T cells and B cells, where it regulates both cell survival and differentiation. During immune responses, TNFRSF21 activation can promote the apoptosis of specific T cell subsets, thereby limiting immune responses and preventing excessive inflammation.
• TNFRSF21 is also involved in B cell differentiation and antibody production. Research suggests that TNFRSF21 helps modulate B cell survival, influencing antibody responses to antigens and potentially regulating autoimmunity.

Role in Nervous System Development and Neurodegeneration:

• In the nervous system, TNFRSF21 is expressed in neurons and glial cells, where it plays a role in synaptic pruning, neuronal apoptosis, and responses to injury. This receptor’s activity in neurons appears to be partly triggered by amyloid precursor protein (APP) cleavage products, which bind to TNFRSF21 and can lead to neuronal apoptosis.
• TNFRSF21-mediated apoptosis in the nervous system has implications for neurodegenerative diseases like Alzheimer’s disease, where excessive cell death is a hallmark. TNFRSF21’s role in neuronal death suggests that it may contribute to neurodegenerative processes when over-activated.

Inflammatory Response:

• In response to infection or inflammation, TNFRSF21 expression can be upregulated in myeloid cells, where it promotes cytokine production and enhances inflammatory responses. TNFRSF21 activation in these cells supports immune defense mechanisms but can also contribute to chronic inflammation if dysregulated.
• By amplifying inflammation, TNFRSF21 is thought to play a role in autoimmune diseases and chronic inflammatory conditions. Studies suggest that excessive TNFRSF21 activation in certain immune cells may lead to tissue damage and perpetuate autoimmune responses.

Clinical Issues

Autoimmune Diseases:

• Overexpression or hyperactivation of TNFRSF21 has been implicated in autoimmune conditions like multiple sclerosis and rheumatoid arthritis. By promoting excessive T cell apoptosis or inflammatory cytokine production, TNFRSF21 contributes to tissue damage and chronic inflammation in these diseases.
• Targeting TNFRSF21 in autoimmune diseases has potential as a therapeutic strategy, with the aim of modulating immune cell survival and reducing inflammation without compromising immune defense.

Neurodegenerative Diseases:

• TNFRSF21’s involvement in neuronal apoptosis links it to neurodegenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis (ALS). The receptor’s activation by amyloid-beta (Aβ) peptides in the brain has been associated with neuronal loss and cognitive decline in Alzheimer’s disease.
• Therapeutic strategies that inhibit TNFRSF21 signaling may help mitigate neuron loss in neurodegenerative diseases. Animal studies have shown that blocking TNFRSF21 can improve cognitive function and reduce Aβ-induced neurotoxicity, suggesting its potential as a target in Alzheimer’s disease therapy.

Cancer:

• TNFRSF21 expression is detected in some cancers, where it may contribute to immune evasion by promoting immune cell apoptosis within the tumor microenvironment. However, its role in cancer is complex and may vary depending on the cancer type.
• Inhibiting TNFRSF21 could potentially boost immune responses against tumors by enhancing immune cell survival and reducing immune suppression within the tumor microenvironment.

Infectious Diseases:

• TNFRSF21 can influence immune responses during infections by modulating T cell apoptosis and cytokine production. In viral infections, TNFRSF21 signaling may be exploited by pathogens to reduce T cell populations and evade immune responses. Its regulation of T cell death and inflammatory responses makes it a potential therapeutic target in viral and bacterial infections.

Summary

TNFRSF21, or DR6, is a member of the TNF receptor superfamily that plays critical roles in apoptosis, immune cell regulation, and inflammatory responses. Structurally, it is composed of an extracellular domain with four cysteine-rich motifs, a transmembrane domain, and an intracellular death domain that facilitates apoptosis through adaptor interactions. Functionally, TNFRSF21 regulates immune responses by modulating T and B cell survival and is essential in apoptotic pathways in both immune and neural cells.

TNFRSF21’s involvement in immune cell apoptosis underpins its role in autoimmune diseases, where excessive activation can lead to chronic inflammation. In the nervous system, its activation by amyloid precursor protein fragments links it to neurodegenerative conditions such as Alzheimer’s disease. Additionally, TNFRSF21 is relevant to cancer biology, where its modulation may affect immune surveillance within tumors.

Therapeutically, targeting TNFRSF21 is an area of interest, as modulating its activity may offer benefits in treating autoimmune disorders, neurodegenerative diseases, and cancers where its function contributes to disease progression.