Regulation of death receptor signaling by the autophagy protein TP 53 INP 2

TP 53 INP 2 positively regulates autophagy by binding to Atg8 proteins. Here, we uncover a novel role of TP 53 INP 2 in death‐receptor signaling. TP 53 INP 2 sensitizes cells to apoptosis induced by death receptor ligands. In keeping with this, TP 53 INP 2 deficiency in cultured cells or mouse livers protects against death receptor‐induced apoptosis. TP 53 INP 2 binds caspase‐8 and the ubiquitin ligase TRAF 6, thereby promoting the ubiquitination and activation of caspase‐8 by TRAF 6. We have defined a TRAF 6‐interacting motif ( TIM ) and a ubiquitin‐interacting motif in TP 53 INP 2, enabling it to function as a scaffold bridging already ubiquitinated caspase‐8 to TRAF 6 for further polyubiquitination of caspase‐8. Mutations of key TIM residues in TP 53 INP 2 abrogate its interaction with TRAF 6 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 TP 53 INP 2 are more prone to TRAIL ‐induced apoptosis, making TP 53 INP 2 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 TP 53 INP 2 as an important regulator of the death receptor pathway.