TRAIL receptor signaling: From the basics of canonical signal transduction toward its entanglement with ER stress and the unfolded protein response.

The cytokine tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the large TNF superfamily that can trigger apoptosis in transformed or infected cells by binding and activating two receptors, TRAIL receptor 1 (TRAILR1) and TRAIL receptor 2 (TRAILR2). Compared to other death ligands of the same family, TRAIL induces apoptosis preferentially in malignant cells while sparing normal tissue and has therefore been extensively investigated for its suitability as an anti-cancer agent. Recently, it was noticed that TRAIL receptor signaling is also linked to endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). The role of TRAIL receptors in regulating cellular apoptosis susceptibility therefore is broader than previously thought. Here, we provide an overview of TRAIL-induced signaling, covering the core signal transduction during extrinsic apoptosis as well as its link to alternative outcomes, such as necroptosis or NF-κB activation. We discuss how environmental factors, transcriptional regulators, and genetic or epigenetic alterations regulate TRAIL receptors and thus alter cellular TRAIL susceptibility. Finally, we provide insight into the role of TRAIL receptors in signaling scenarios that engage the unfolded protein response and discuss how these findings might be translated into new combination therapies for cancer treatment.