Mitochondria to nucleus stress signaling: a distinctive mechanism of NFkappaB/Rel activation through calcineurin-mediated inactivation of IkappaBbeta.
Mitochondria to nucleus stress signaling: a distinctive mechanism of NFkappaB/Rel activation through calcineurin-mediated inactivation of IkappaBbeta.
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DOI：
10.1083/jcb.200211104
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发表时间：
2003-05-12
期刊：
影响因子：
--
通讯作者：
Avadhani NG
中科院分区：
文献类型：
--
作者：
Biswas G;Anandatheerthavarada HK;Zaidi M;Avadhani NG
线粒体遗传和代谢应激导致钙调磷酸酶（Cn）、NFAT、ATF2和NFκB/Rel因子的激活，这些因子共同改变了一系列核基因的表达。我们在这里证明，线粒体应激诱导的nf - κ b /Rel因子激活涉及通过cn介导的去磷酸化使i - κ b β失活。磷酸化的IκBβ是Cn磷酸酶的底物，被FK506和RII肽抑制。化学交联和共免疫沉淀表明，在体外和体内条件下，NFκB/Rel因子结合的i - κ b β与Cn形成对FK506敏感的三元配合物。结果表明，ikb β cooh末端PEST结构域的S313和S315位点磷酸化是与Cn结合的关键。IκBβ的S313/S315位点突变可抑制Cn结合，抑制Cn介导的细胞核内Rel蛋白的增加，并对线粒体应激诱导的RyR1和组织蛋白酶L基因的表达产生显性负向影响。我们的研究结果表明，线粒体应激诱导的NFκB/Rel活化具有独特的性质，它独立于IKKα和IKKβ激酶，并影响与细胞因子和tnf α诱导的应激信号不同的基因靶点。这些结果为Cn作为Ca2+信号传导和NFκB/Rel激活之间的关键联系提供了新的见解。
Mitochondrial genetic and metabolic stress causes activation of calcineurin (Cn), NFAT, ATF2, and NFκB/Rel factors, which collectively alter the expression of an array of nuclear genes. We demonstrate here that mitochondrial stress–induced activation of NFκB/Rel factors involves inactivation of IκBβ through Cn-mediated dephosphorylation. Phosphorylated IκBβ is a substrate for Cn phosphatase, which was inhibited by FK506 and RII peptide. Chemical cross-linking and coimmunoprecipitation show that NFκB/Rel factor–bound IκBβ forms a ternary complex with Cn under in vitro and in vivo conditions that was sensitive to FK506. Results show that phosphorylation at S313 and S315 from the COOH-terminal PEST domain of IκBβ is critical for binding to Cn. Mutations at S313/S315 of IκBβ abolished Cn binding, inhibited Cn-mediated increase of Rel proteins in the nucleus, and had a dominant-negative effect on the mitochondrial stress–induced expression of RyR1 and cathepsin L genes. Our results show the distinctive nature of mitochondrial stress–induced NFκB/Rel activation, which is independent of IKKα and IKKβ kinases and affects gene target(s) that are different from cytokine and TNFα-induced stress signaling. The results provide new insights into the role of Cn as a critical link between Ca2+ signaling and NFκB/Rel activation.
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