Activation of the Akt-NF-kappaB pathway by subtilase cytotoxin through the ATF6 branch of the unfolded protein response.
Activation of the Akt-NF-kappaB pathway by subtilase cytotoxin through the ATF6 branch of the unfolded protein response.
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DOI：
10.4049/jimmunol.0900017
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发表时间：
2009-07-15
期刊：
影响因子：
--
通讯作者：
Kitamura M
中科院分区：
文献类型：
--
作者：
Yamazaki H;Hiramatsu N;Hayakawa K;Tagawa Y;Okamura M;Ogata R;Huang T;Nakajima S;Yao J;Paton AW;Paton JC;Kitamura M
滋贺毒素具有诱导炎症相关基因表达的潜力，但其潜在机制尚不清楚。我们研究了枯草杆菌酶细胞毒素（SubAB）对NF-κB活化的影响。SubAB是由某些滋贺致突变大肠杆菌产生的AB 5毒素。已知SubAB是选择性降解GRP 78/Bip的蛋白酶。用SubAB处理NRK-52 E细胞引起GRP 78的快速切割。在GRP 78降解后，观察到NF-κB的瞬时活化，在6-12 h达到峰值;尽管持续缺乏完整的GRP 78，但活化在24 h内消退。NF-κB的活化先于Akt的瞬时磷酸化。用选择性Akt 1/2抑制剂或PI 3 K抑制剂处理细胞可减弱SubAB诱导的NF-κB活化，表明Akt活化是NF-κB上游的事件。GRP 78降解引起未折叠蛋白反应（UPR），UPR诱导剂模拟SubAB对Akt和NF-κB的刺激作用。SubAB触发了UPR的三个主要分支，包括IRE 1-XBP 1、PERK和ATF 6通路。显性负性抑制IRE 1 α、XBP 1或PERK不会减弱SubAB对NF-κB的激活。相反，ATF 6的遗传和药理学抑制显著抑制SubAB触发的Akt磷酸化和NF-κB活化。这些结果表明，由SubAB引起的GRP 78的丢失导致Akt的瞬时磷酸化，并随后通过UPR的ATF 6分支激活NF-κB。
Shiga toxin has the potential to induce expression of inflammation-associated genes, although the underlying mechanisms are not well understood. We examined the effects of subtilase cytotoxin (SubAB), an AB5 toxin produced by some Shiga toxigenic Escherichia coli, on the activation of NF-κB. SubAB is known to be a protease which selectively degrades GRP78/Bip. Treatment of NRK-52E cells with SubAB caused rapid cleavage of GRP78. Following the degradation of GRP78, transient activation of NF-κB was observed with a peak at 6–12 h; the activation subsided within 24 h despite the continuous absence of intact GRP78. The activation of NF-κB was preceded by transient phosphorylation of Akt. Treatment of the cells with a selective inhibitor of Akt1/2 or an inhibitor of PI3K attenuated SubAB-induced NF-κB activation, suggesting that activation of Akt is an event upstream of NF-κB. Degradation of GRP78 caused the unfolded protein response (UPR), and inducers of the UPR mimicked the stimulatory effects of SubAB on Akt and NF-κB. SubAB triggered the three major branches of the UPR including the IRE1-XBP1, PERK, and ATF6 pathways. Dominant-negative inhibition of IRE1α, XBP1, or PERK did not attenuate activation of NF-κB by SubAB. In contrast, genetic and pharmacological inhibition of ATF6 significantly suppressed SubAB-triggered Akt phosphorylation and NF-κB activation. These results suggested that loss of GRP78 by SubAB leads to transient phosphorylation of Akt and consequent activation of NF-κB through the ATF6 branch of the UPR.
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影响因子：
4.4
作者：
Hayakawa, Kunihiro;Hiramatsu, Nobuhiko;Kitamura, Masanori
通讯作者：
Kitamura, Masanori
影响因子：
4.8
作者：
Katayama, T;Imaizumi, K;Tohyama, M
通讯作者：
Tohyama, M
影响因子：
82.9
作者：
Iwawaki, T;Akai, R;Miura, M
通讯作者：
Miura, M
影响因子：
2
作者：
Kaneko, M;Niinuma, Y;Nomura, Y
通讯作者：
Nomura, Y
影响因子：
19.6
作者：
Meng, YM;Kasai, A;Kitamura, M
通讯作者：
Kitamura, M