Inoue Masaki, Kamada Haruhiko, Abe Yasuhiro, Higashisaka Kazuma, Nagano Kazuya, Mukai Yohei, Yoshioka Yasuo, Tsutsumi Yasuo, Tsunoda Shin-Ichi
Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.
Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan The Center for Advanced Medical Engineering and Informatics, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
J Cell Sci. 2015 Feb 15;128(4):656-69. doi: 10.1242/jcs.149385. Epub 2015 Jan 20.
Tumor necrosis factor (TNF) is an important mediator that triggers onset of autoimmune diseases and exerts its biological effects by interacting through two receptors, TNFR1 (also known as TNFRSF1A) and TNFR2 (also known as TNFRSF1B). TNFR2 signaling has significant potential to exert pro-survival and protective roles in several diseases. Unlike TNFR1 signaling, however, the mechanism of TNFR2 signal transduction is poorly understood, and few of its adaptor molecules are known. The present study utilized a proteomics approach to search for adaptor molecules in the TNFR2 signaling complex and identified aminopeptidase P3 (APP3, also known as XPNPEP3) to be a key molecule. One of its two isoforms, mitochondrial APP3 (APP3m) but not cytosolic APP3 (APP3c), was recruited to TNFR2 and shown to regulate TNF-TNFR2-dependent phosphorylation of JNK1 (also known as MAPK8) and JNK2 (also known as MAPK9). Furthermore, APP3m was released from mitochondria upon TNF stimulation in the absence of mitochondrial outer membrane permeabilization (MOMP). The observation of increased cell death upon downregulation of APP3m also suggested that APP3m exerts an anti-apoptotic function. These findings reveal that APP3m is a new member of the TNF-TNFR2 signaling complex and characterize an APP3-mediated TNFR2 signal transduction mechanism that induces activation of JNK1 and JNK2.
肿瘤坏死因子（TNF）是一种重要的介质，它触发自身免疫性疾病的发作，并通过与两种受体相互作用发挥其生物学效应，这两种受体分别是TNFR1（也称为TNFRSF1A）和TNFR2（也称为TNFRSF1B）。TNFR2信号传导在几种疾病中具有显著的促生存和保护作用。然而，与TNFR1信号传导不同，TNFR2信号转导的机制尚不清楚，其衔接分子也很少为人所知。本研究利用蛋白质组学方法在TNFR2信号复合物中寻找衔接分子，并确定氨肽酶P3（APP3，也称为XPNPEP3）是关键分子。其两种同工型之一，线粒体APP3（APP3m）而非胞质APP3（APP3c），被招募到TNFR2，并显示出调节TNF-TNFR2依赖性的JNK1（也称为MAPK8）和JNK2（也称为MAPK9）磷酸化。此外，在没有线粒体外膜通透性改变（MOMP）的情况下，TNF刺激后APP3m从线粒体释放。下调APP3m后细胞死亡增加的观察结果也表明APP3m发挥抗凋亡功能。这些发现揭示APP3m是TNF-TNFR2信号复合物的新成员，并阐明了一种由APP3介导的TNFR2信号转导机制，该机制可诱导JNK1和JNK2的激活。
