Regulation of death receptor signaling by the autophagy protein TP53INP2

Abstract TP53INP2 positively regulates autophagy by binding to Atg8 proteins. Here, we uncover a novel role of TP53INP2 in death‐receptor signaling. TP53INP2 sensitizes cells to apoptosis induced by death receptor ligands. In keeping with this, TP53INP2 deficiency in cultured cells or mouse livers protects against death receptor‐induced apoptosis. TP53INP2 binds caspase‐8 and the ubiquitin ligase TRAF6, thereby promoting the ubiquitination and activation of caspase‐8 by TRAF6. We have defined a TRAF6‐interacting motif (TIM) and a ubiquitin‐interacting motif in TP53INP2, enabling it to function as a scaffold bridging already ubiquitinated caspase‐8 to TRAF6 for further polyubiquitination of caspase‐8. Mutations of key TIM residues in TP53INP2 abrogate its interaction with TRAF6 and caspase‐8, and subsequently reduce levels of death receptor‐induced apoptosis. A screen of cancer cell lines showed that those with higher protein levels of TP53INP2 are more prone to TRAIL‐induced apoptosis, making TP53INP2 a potential predictive marker of cancer cell responsiveness to TRAIL treatment. These findings uncover a novel mechanism for the regulation of caspase‐8 ubiquitination and reveal TP53INP2 as an important regulator of the death receptor pathway.