Cell death leaves a new TRAIL

Abstract

Cell death involves numerous mechanisms that can be cross-regulated through a complex signaling network. In this issue, Bozkurt et al. (2021. J. Cell Biol.https://doi.org/10.1083/jcb.202010030) identify a new connection in the network: signaling from TRAIL, a canonical inducer of apoptosis, can also induce a form of cell death called entosis, which has implications for cancer progression.

Figure 1.

A new TRAIL of cell death. Signaling from TRAIL through its receptors (DR4/5) is well known to induce apoptosis (left path) by a mechanism involving formation of a death-induced signaling complex involving fas-associated death domain protein (FADD) and caspase-8, and subsequent activation of caspase-8 activity that leads to cell death. Bozkurt et al. now discover that TRAIL can also induce entosis (right path) through a mechanism requiring DR4/5 and a noncatalytic function of caspase-8 (6). Whereas apoptosis is executed in a cell-autonomous manner and is largely anti-inflammatory, entosis is executed in a non-cell-autonomous manner and is competitive between cells.