Selection of autophagy or apoptosis in cells exposed to ER-stress depends on ATF4 expression pattern with or without CHOP expression.
Selection of autophagy or apoptosis in cells exposed to ER-stress depends on ATF4 expression pattern with or without CHOP expression.
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DOI：
10.1242/bio.20135033
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发表时间：
2013
期刊：
影响因子：
2.4
通讯作者：
Matsuo S
中科院分区：
文献类型：
--
作者：
Matsumoto H;Miyazaki S;Matsuyama S;Takeda M;Kawano M;Nakagawa H;Nishimura K;Matsuo S
暴露于ER-应激的细胞经历未折叠蛋白反应（UPR）以避免凋亡，但也可能激活自噬。然而，选择这两种保护性反应之一的信号是未知的。为了阐明自噬和凋亡之间的关键开关，我们研究了UPR相关信号与HepG 2细胞中自噬和/或凋亡诱导的相关性，这些细胞暴露于三种ER应激诱导剂（NaF，衣霉素和毒胡萝卜素）随时间的变化，包括小干扰RNA对细胞反应的影响。Thapsiglavin诱导的ER应激仅在12小时后引起细胞凋亡，伴随Ire 1磷酸化，Grp 78，ATF 4和CHOP表达。 另一方面，NaF和衣霉素诱导的ER应激仅在28小时的早期阶段引起具有ATF 4表达和没有CHOP表达的自噬。 ATF 4-siRNA可完全抑制NaF或衣霉素诱导的自噬，同时抑制ATF 4蛋白和mRNA的表达，也可抑制毒胡萝卜素诱导的细胞凋亡，同时抑制ATF 4和CHOP的表达。CHOP-siRNA对NaF和衣霉素激活的自噬没有影响。另一方面，CHOP-siRNA在毒胡萝卜素诱导的ER应激中激活自噬，具有显著的ATF 4表达，并且通过CHOP抑制来抑制凋亡。这些结果表明，ATF 4是ER应激诱导的自噬的关键信号，并且自噬通过随后的CHOP上调而转换为凋亡，这表明自噬和凋亡之间的转换开关位于PERK通路中的ATF 4到CHOP之间。
Cells exposed to ER-stress undergo the Unfolded Protein Response (UPR) to avoid apoptosis, but may also activate autophagy. However, the signal for selection of one of these two protective responses is unknown. To clarify the key switch between autophagy and apoptosis, we examined the correlation of UPR-related signals with autophagy and/or apoptosis inductions in HepG2 cells exposed to three ER-stress inducers (NaF, tunicamycin, and thapsigargin) with time, including the effect of small interfering RNA on the cell responses. Thapsigargin-induced ER-stress caused only apoptosis after ∼2 hr with Ire1 phosphorylation, and Grp78, ATF4, and CHOP expressions. On the other hand, NaF- and tunicamycin-induced ER-stress caused only autophagy in the early stage by ∼8 hr with ATF4 expression and without CHOP expression. ATF4-siRNA completely inhibited the autophagy induced by NaF or tunicamycin with suppressed ATF4 protein and mRNA expressions, and also inhibited apoptosis by thapsigargin with suppression of both ATF4 and CHOP. CHOP-siRNA had no effect on autophagy activation by NaF and tunicamycin. On the other hand, CHOP-siRNA activated autophagy in thapsigargin-induced ER-stress with significant ATF4 expression, and suppressed apoptosis with CHOP suppression. These results showed that ATF4 is the key signal for autophagy induced by ER-stress, and that autophagy is switched to apoptosis by subsequent CHOP upregulation, suggesting that the changeover switch between autophagy and apoptosis is located between ATF4 to CHOP in the PERK pathway.
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DOI：
10.1074/jbc.m109.014092
发表时间：
2010-02-26
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Armstrong JL;Flockhart R;Veal GJ;Lovat PE;Redfern CP
通讯作者：
Redfern CP
影响因子：
8
作者：
Rzymski, T.;Milani, M.;Harris, A. L.
通讯作者：
Harris, A. L.
影响因子：
5.3
作者：
Blais, JD;Filipenko, V;Bell, JC
通讯作者：
Bell, JC
影响因子：
13.3
作者：
Semenza, Gregg L.
通讯作者：
Semenza, Gregg L.
影响因子：
64.8
作者：
Kuma, A;Hatano, M;Mizushima, N
通讯作者：
Mizushima, N