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EMBO J ; 38(10)2019 05 15.
Article in English | MEDLINE | ID: mdl-30979779

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.


Subject(s)
Autophagy/genetics , Nuclear Proteins/physiology , Animals , Apoptosis/drug effects , Apoptosis/genetics , Autophagy/drug effects , Caspase 8/metabolism , Cells, Cultured , HEK293 Cells , HeLa Cells , Humans , Intracellular Signaling Peptides and Proteins , MCF-7 Cells , Mice , Mice, Inbred C57BL , Mice, Knockout , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/pathology , Nuclear Proteins/genetics , Receptors, Death Domain/genetics , Receptors, Death Domain/metabolism , Signal Transduction/genetics , TNF Receptor-Associated Factor 6/metabolism , TNF-Related Apoptosis-Inducing Ligand/pharmacology , TNF-Related Apoptosis-Inducing Ligand/therapeutic use , Ubiquitin/metabolism , Ubiquitination/drug effects , Ubiquitination/genetics
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