Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain.
EMBO J. 2019 May 15;38(10). doi: 10.15252/embj.201899300. Epub 2019 Apr 12.
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.
TP53INP2 通过与 Atg8 蛋白结合正向调节自噬。在这里，我们揭示了 TP53INP2 在死亡受体信号中的一个新作用。TP53INP2 使细胞对死亡受体配体诱导的细胞凋亡敏感。与此一致的是，培养细胞或小鼠肝脏中 TP53INP2 的缺失可防止死亡受体诱导的细胞凋亡。TP53INP2 与半胱天冬酶-8 和泛素连接酶 TRAF6 结合，从而促进 TRAF6 对半胱天冬酶-8 的泛素化和激活。我们已经定义了 TP53INP2 中的 TRAF6 相互作用基序（TIM）和泛素相互作用基序，使其能够作为桥接已经泛素化的半胱天冬酶-8 与 TRAF6 的支架，从而进一步对半胱天冬酶-8 进行多泛素化。TP53INP2 中的关键 TIM 残基的突变会使其丧失与 TRAF6 和半胱天冬酶-8 的相互作用，随后降低死亡受体诱导的细胞凋亡水平。对癌细胞系的筛选表明，那些具有更高水平 TP53INP2 蛋白的细胞更容易受到 TRAIL 诱导的凋亡，这使得 TP53INP2 成为 TRAIL 治疗对癌细胞反应性的潜在预测标志物。这些发现揭示了 caspase-8 泛素化调节的新机制，并揭示了 TP53INP2 作为死亡受体途径的重要调节剂。
