Anthrax lethal toxin promotes dephosphorylation of TTP and formation of processing bodies.
Anthrax lethal toxin promotes dephosphorylation of TTP and formation of processing bodies.
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DOI：
10.1111/j.1462-5822.2009.01418.x
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发表时间：
2010-04-01
影响因子：
3.4
通讯作者：
Mogridge J
中科院分区：
文献类型：
--
作者：
Chow EM;Batty S;Mogridge J
炭疽致死毒素（LeTx）由保护性抗原（PA）和致死因子（LF）组成，PA是受体结合部分，LF是切割丝裂原活化蛋白激酶（MAPKKs）的蛋白酶。LeTx破坏了对B的免疫反应。炭疽病的作用机制主要有几种，如通过增加IL-8 mRNA降解速率下调IL-8。许多转录物通过顺式作用元件调节，顺式作用元件结合阻碍或促进降解的蛋白质。这些RNA结合蛋白中的一些由MAPK调节，并且先前的工作已经证明干扰MAPK信号传导降低IL-8 mRNA的半衰期。在此，我们定位了IL-8 3′非翻译区中负责LeTx诱导的转录不稳定的片段，并表明这是由p38、ERK和JNK通路的抑制引起的。TTP是一种参与IL-8 mRNA衰变的RNA结合蛋白，在LeTx处理的细胞中变得低磷酸化，并且TTP的敲低阻止LeTx使IL-8转录物不稳定。用LeTx处理的细胞表现出TTP对加工体的定位增加，加工体是积累靶向降解的转录物的结构。我们还观察到LeTx促进了加工体的形成，揭示了毒素与主要mRNA衰变途径之间的联系。
Anthrax lethal toxin (LeTx) is composed of protective antigen (PA) and lethal factor (LF) – PA is the receptor-binding moiety and LF is a protease that cleaves mitogen-activated protein kinase kinases (MAPKKs). LeTx subverts the immune response to B. anthracis in several ways, such as downregulating interleukin-8 (IL-8) by increasing the rate of IL-8 mRNA degradation. Many transcripts are regulated through cis-acting elements that bind proteins that either impede or promote degradation. Some of these RNA binding proteins are regulated by MAPKs and previous work has demonstrated that interfering with MAPK signaling decreases the half-life of IL-8 mRNA. Here, we have localized a segment within the IL-8 3′ untranslated region responsible for LeTx-induced transcript destabilization and show that this is caused by inhibition of the p38, ERK, and JNK pathways. TTP, an RNA binding protein involved in IL-8 mRNA decay, became hypophosphorylated in LeTx-treated cells and knock-down of TTP prevented LeTx from destabilizing the IL-8 transcript. Cells that were treated with LeTx exhibited increased localization of TTP to Processing-bodies, which are structures that accumulate transcripts targeted for degradation. We furthermore observed that LeTx promoted the formation of Processing-bodies, revealing a link between the toxin and a major mRNA decay pathway.
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影响因子：
14.9
作者：
Bakheet T;Williams BR;Khabar KS
通讯作者：
Khabar KS
影响因子：
2.9
作者：
Miller, CJ;Elliott, JL;Collier, RJ
通讯作者：
Collier, RJ
影响因子：
4.8
作者：
Lai, WS;Carballo, E;Blackshear, PJ
通讯作者：
Blackshear, PJ
影响因子：
15.3
作者：
Paccani, SR;Tonello, F;Baldari, CT
通讯作者：
Baldari, CT
影响因子：
3.3
作者：
Eystathioy, T;Chan, EKL;Fritzler, MJ
通讯作者：
Fritzler, MJ