TNFRSF10C

TNFRSF10C Full Name

tumor necrosis factor receptor superfamily, member 10c, decoy without an intracellular domain

TNFRSF10C Introduction

TNFRSF10C encodes TRAIL receptor 3 (TRAIL-R3), also known as DcR1 or LIT, one of the receptors for the cytokine TRAIL (TNF-related apoptosis-inducing ligand). TRAIL is best known for its ability to kill tumor cells while sparing most normal cells, an activity that is mediated through its death receptors, which signal apoptosis upon ligand binding. TRAIL-R3, however, is a decoy receptor: it binds TRAIL on the cell surface but lacks a functional intracellular signaling domain and therefore cannot transmit a death signal. By sequestering TRAIL and competing with the death receptors for ligand, TRAIL-R3 protects cells that express it from TRAIL-induced apoptosis. The receptor is unusual even among decoys because it is attached to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor rather than a transmembrane segment, and it is encoded by a gene that sits in a chromosomal cluster together with the TRAIL death receptors DR4 and DR5 and the second decoy DcR2. Because many tumor cells express TRAIL-R3, the decoy receptor is an important determinant of TRAIL sensitivity, and its expression has been linked to resistance to TRAIL-based cancer therapies. Conversely, the restricted expression of TRAIL-R3 on normal cells contributes to the selectivity of TRAIL as a potential anticancer agent, making the balance between death and decoy receptors a central theme in the biology of this cytokine.

Figure 1. Overview and function of of TNFRSF10C.

Cysteine-Rich Receptor Architecture and GPI Membrane Anchoring
TRAIL-R3 is a member of the tumor necrosis factor receptor superfamily, whose members are characterized by extracellular cysteine-rich domains that form the ligand-binding scaffold.
The extracellular region of TRAIL-R3 contains multiple cysteine-rich repeats that adopt the elongated, disulfide-stabilized structure typical of TNFR family members and that mediate high-affinity binding to the trimeric TRAIL ligand.
Unlike the death receptors DR4 and DR5, which possess a cytoplasmic death domain required for apoptosis signaling, TRAIL-R3 has only a very short cytoplasmic tail that lacks signaling function.
The mature receptor is attached to the outer leaflet of the plasma membrane through a glycosylphosphatidylinositol (GPI) anchor, which confers the protein with lateral mobility within the membrane and targets it to lipid-rich microdomains.
The TNFRSF10C gene is located on human chromosome 8 within a cluster of TRAIL receptor genes, and this genomic region has been linked to susceptibility to certain cancers.
TRAIL-R3 can also exist in soluble form, generated by proteolytic cleavage or alternative splicing, and soluble decoy receptors can neutralize TRAIL in the extracellular space.
The stoichiometry of ligand binding is shared among the TRAIL receptors, so the relative abundance of death versus decoy receptors on a cell determines the outcome of TRAIL engagement.

TRAIL Signaling, Apoptosis Resistance, and Cancer Therapy
TRAIL induces apoptosis by clustering the death receptors DR4 and DR5, which recruit the adaptor FADD and initiator caspases to form the death-inducing signaling complex; decoy receptors such as TRAIL-R3 blunt this process by competing for ligand.
Cells that express high levels of TRAIL-R3 are relatively resistant to TRAIL, and many tumor cell lines owe part of their TRAIL resistance to the expression of decoy receptors.
The GPI anchor of TRAIL-R3 may also allow the receptor to sequester TRAIL within membrane microdomains and to influence the signaling of the death receptors through their spatial organization.
Clinical interest in TRAIL stems from its ability to kill transformed cells selectively, and recombinant TRAIL and agonistic antibodies against the death receptors have been evaluated as cancer therapies; the expression of TRAIL-R3 in tumors is among the factors that determine responsiveness.
In normal physiology, TRAIL and its receptors participate in immune surveillance against tumors and in the regulation of immune responses, and decoy receptors help protect healthy tissues from collateral damage during immune activation.
Measuring the balance of TRAIL receptor isoforms in tumors, including TNFRSF10C, is being explored as a way to predict which patients are most likely to benefit from TRAIL-based or death-receptor-targeted therapies.

Alternate Names for TNFRSF10C

TNFRSF10C; tumor necrosis factor receptor superfamily, member 10c, decoy without an intracellular domain; LIT; DCR1; TRID; CD263; TRAILR3; TRAIL-R3; DCR1-TNFR; tumor necrosis factor receptor superfamily member 10C