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.
Dokumententyp: | Zeitschriftenartikel |
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Fakultät: | Medizin
Medizin > Munich Cluster for Systems Neurology (SyNergy) |
Themengebiete: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit |
URN: | urn:nbn:de:bvb:19-epub-81492-1 |
ISSN: | 0261-4189 |
Sprache: | Englisch |
Dokumenten ID: | 81492 |
Datum der Veröffentlichung auf Open Access LMU: | 15. Dez. 2021, 14:59 |
Letzte Änderungen: | 10. Jun. 2024, 05:50 |
DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198 |