Schurmans Stéphane, Pouillon Valérie, Maréchal Yoann
Institut de Recherches Interdisciplinaires en Biologie Humaine et Moléculaire (IRIBHM), Faculté de Médecine, Université Libre de Bruxelles, Gosselies, Belgium.
Adv Enzyme Regul. 2011;51(1):66-73. doi: 10.1016/j.advenzreg.2010.08.001. Epub 2010 Oct 28.
In mammals, Ins(1,4,5)P3, the well known calcium mobilization messenger, is phosphorylated in the cytosol at the 3-position of the inositol ring to yield Ins(1,3,4,5)P4 by Ins(1,4,5)P3 3-kinases A, B and C isoforms as well as by inositol polyphosphate multikinase (Ipmk). Studies in gene-deficient mice have revealed that these enzymes and Ins(1,3,4,5)P4, their reaction product, play essential role in multiple physiological processes, ranging from synaptic plasticity, hematopoietic cell survival, development and function, to mRNA export, transcriptional regulation and chromatin remodelling. Rather than to provide an unique and “universal” mechanism of Ins(1,3,4,5)P4 action, these studies in genetically-modified mice point for a role of this inositide in the control of calcium mobilization, of the subcellular localisation of PH domain-containing target proteins, and of higher inositol phosphate production. Mice deficient for the B isoform of inositol 1,4,5-trisphosphate 3-kinase (Itpkb) develop profound alterations in T and B cells as well as in neutrophils and mast cells. Our recent studies indicate that the 3-kinase Itpkb and Ins(1,3,4,5)P4 are important for the survival of naïve mature B cells and the control of proapoptotic Bim protein expression, rather than for the control of B cell transition from one developmental stage to another. They also suggest that Itpkb is an important component in the control of B cell anergy.
在哺乳动物中，众所周知的钙动员信使肌醇-1,4,5-三磷酸（Ins(1,4,5)P3）在胞质溶胶中，于肌醇环的3位被磷酸化，通过肌醇-1,4,5-三磷酸3激酶A、B和C亚型以及肌醇多磷酸多激酶（Ipmk）生成肌醇-1,3,4,5-四磷酸（Ins(1,3,4,5)P4）。对基因缺陷小鼠的研究表明，这些酶及其反应产物Ins(1,3,4,5)P4在多种生理过程中发挥着重要作用，范围从突触可塑性、造血细胞存活、发育和功能，到mRNA输出、转录调控和染色质重塑。这些对基因改造小鼠的研究并非要提供Ins(1,3,4,5)P4作用的独特且“通用”机制，而是指出这种肌醇磷酸酯在控制钙动员、含PH结构域的靶蛋白亚细胞定位以及更高阶肌醇磷酸生成方面的作用。肌醇-1,4,5-三磷酸3激酶（Itpkb）B亚型缺陷的小鼠在T细胞、B细胞以及中性粒细胞和肥大细胞中出现了深刻的变化。我们最近的研究表明，3激酶Itpkb和Ins(1,3,4,5)P4对幼稚成熟B细胞的存活以及促凋亡Bim蛋白表达的控制很重要，而不是对B细胞从一个发育阶段向另一个发育阶段的转变的控制。这些研究还表明，Itpkb是控制B细胞无能的一个重要组成部分。
