The PEA-15 Protein Regulates Autophagy via Activation of JNK
The PEA-15 Protein Regulates Autophagy via Activation of JNK
复制标题
DOI：
10.1074/jbc.m109.096628
复制
发表时间：
2010-07-09
影响因子：
4.8
通讯作者：
Roth, Wilfried
中科院分区：
文献类型：
--
作者：
Boeck, Barbara C.;Tagscherer, Katrin E.;Roth, Wilfried
PEA-15/PED(富含15 kDa星形胶质细胞的磷酸化蛋白/糖尿病富含的磷酸化蛋白)是一种含有死亡效应结构域的蛋白，可调节细胞的死亡。PEA-15抑制caspase激活和增强ERK(细胞外调节激酶)活性的机制已经被很好地描述。在这里，我们证明了PEA-15不仅在ERK通路的激活中起关键作用，而且还调节JNK(c-jun氨基末端激酶)信号。当PEA-15在恶性胶质瘤细胞中过表达时，JNK被有效地激活。PEA-15诱导的JNK激活依赖于PEA-15在两个磷酸化位点(丝氨酸104和丝氨酸116)的磷酸化。SiRNA介导的内源性PEA-15的下调实质上抑制了JNK的激活。此外，我们证明，过度表达PEA-15的胶质瘤细胞在经典的自噬刺激下表现出更多的自噬迹象，如电离辐射、血清剥夺或雷帕霉素治疗。相反，PEA-15的非磷酸化突变体不能促进自噬。对JNK的抑制消除了PEA-15介导的自噬增加。总之，我们的数据表明，PEA-15以JNK依赖的方式促进胶质瘤细胞的自噬。这可能会使胶质瘤细胞对饥饿或电离辐射等不利刺激更具抵抗力。
PEA-15/PED (phosphoprotein enriched in astrocytes 15 kDa/phosphoprotein enriched in diabetes) is a death effector domain-containing protein which is known to modulate apoptotic cell death. The mechanism by which PEA-15 inhibits caspase activation and increases ERK (extracellular-regulated kinase) activity is well characterized. Here, we demonstrate that PEA-15 is not only pivotal in the activation of the ERK pathway but also modulates JNK (c-Jun N-terminal kinase) signaling. Upon overexpression of PEA-15 in malignant glioma cells, JNK is potently activated. The PEA-15-induced JNK activation depends on the phosphorylation of PEA-15 at both phosphorylation sites (serine 104 and serine 116). The activation of JNK is substantially inhibited by siRNA-mediated down-regulation of endogenous PEA-15. Moreover, we demonstrate that glioma cells overexpressing PEA-15 show increased signs of autophagy in response to classical autophagic stimuli such as ionizing irradiation, serum deprivation, or rapamycin treatment. In contrast, the non-phosphorylatable mutants of PEA-15 are not capable of promoting autophagy. The inhibition of JNK abrogates the PEA-15-mediated increase in autophagy. In conclusion, our data show that PEA-15 promotes autophagy in glioma cells in a JNK-dependent manner. This might render glioma cells more resistant to adverse stimuli such as starvation or ionizing irradiation.