Maruoka Shuichiro, Hashimoto Shu, Gon Yasuhiro, Nishitoh Hideki, Takeshita Ikuko, Asai Yasukiyo, Mizumura Kenji, Shimizu Kazufumi, Ichijo Hidenori, Horie Takashi
First Department of Internal Medicine, Nihon University School of Medicine, 30-1 Oyaguchikamimachi, Itabashi-ku, Tokyo 173-8610, Japan.
Biochem Biophys Res Commun. 2003 Aug 8;307(4):870-6. doi: 10.1016/s0006-291x(03)01283-x.
Apoptosis occurs in influenza virus (IV)-infected cells. There are a number of mechanisms for the regulation of apoptosis. However, the molecular mechanism of IV infection-induced apoptosis is still controversial. Apoptosis signal-regulating kinase1 (ASK1) is a ubiquitously expressed mitogen-activated protein kinase kinase kinase (MAPKKK) that activates the SEK1-c-Jun N-terminal kinase (JNK) and MKK3/MKK6-p38 MAPK signaling cascades. ASK1 has been implicated in cytokine- and stress-induced apoptosis. Here, we show the following: (1) IV infection activated ASK1 and concomitantly phosphorylated JNK and p38 MAPK in human bronchial epithelial cells; (2) the activation of JNK and p38 MAPK but not extracellular-regulated kinase (ERK) in embryonic fibroblasts (MEFs) derived from ASK1 knockout mice (ASK1(-/-) MEFs) was depressed compared to MEFs derived from wild type mice (ASK1(+/+) MEFs); and (3) ASK1(-/-) MEFs were defective in IV infection-induced caspase-3 activation and cell death. These results indicate that apoptosis in IV-infected BEC is mediated through ASK1-dependent cascades.
凋亡发生在流感病毒（IV）感染的细胞中。凋亡的调控存在多种机制。然而，IV感染诱导凋亡的分子机制仍存在争议。凋亡信号调节激酶1（ASK1）是一种广泛表达的丝裂原活化蛋白激酶激酶激酶（MAPKKK），可激活SEK1 - c - Jun氨基末端激酶（JNK）和MKK3/MKK6 - p38 MAPK信号级联反应。ASK1与细胞因子和应激诱导的凋亡有关。在此，我们展示以下内容：（1）IV感染激活了人支气管上皮细胞中的ASK1，并同时使JNK和p38 MAPK磷酸化；（2）与源自野生型小鼠的胚胎成纤维细胞（ASK1(+/+) MEFs）相比，源自ASK1基因敲除小鼠的胚胎成纤维细胞（ASK1(-/-) MEFs）中JNK和p38 MAPK的激活受到抑制，但细胞外调节激酶（ERK）未受影响；（3）ASK1(-/-) MEFs在IV感染诱导的caspase - 3激活和细胞死亡方面存在缺陷。这些结果表明，IV感染的支气管上皮细胞中的凋亡是通过ASK1依赖性级联反应介导的。
