TRAILR4

TRAIL receptor 4 (TRAIL-R4), also known as TNFRSF10D, is a member of the tumor necrosis factor receptor (TNFR) superfamily in humans. It is encoded by the TNFRSF10D gene and is commonly described as a decoy receptor for TRAIL (TNF-related apoptosis-inducing ligand).

TRAIL-R4 is a type I membrane protein with extracellular cysteine-rich domains that bind TRAIL, but it lacks a functional cytoplasmic death domain. Consequently, engagement by TRAIL does not trigger apoptosis through TRAIL-R4, and the receptor primarily acts by sequestering TRAIL away from death-inducing receptors DR4 and DR5.

Role in cells: By competing for TRAIL, TRAIL-R4 can dampen TRAIL-induced apoptotic signaling, potentially modulating cell survival in tissues. In several cancer cell lines, high TRAIL-R4 expression correlates with reduced sensitivity to TRAIL and to TRAIL-based therapies, making it a possible mechanism of resistance.

Expression and clinical relevance: TRAIL-R4 is detected in a range of normal tissues and is often dysregulated in tumors. Because of its decoy function, the receptor is a focus of research aimed at improving TRAIL-based treatment strategies, for example by combining TRAIL with agents that downregulate TRAIL-R4 or block its activity.

History: The TNFRSF10D gene encoding TRAIL-R4 was identified in the late 1990s/early 2000s as part of the expanding TRAIL signaling system.