Brief Definitive Report the Transcription Factor Xbp-1 Is Essential for the Development and Survival of Dendritic Cells
Brief Definitive Report the Transcription Factor Xbp-1 Is Essential for the Development and Survival of Dendritic Cells
复制标题
DOI：
--
复制
发表时间：
--
期刊：
影响因子：
--
通讯作者：
L. Glimcher;N. Iwakoshi;M. Pypaert
中科院分区：
文献类型：
--
作者：
L. Glimcher;N. Iwakoshi;M. Pypaert
从ER发出的信号诱导转录程序，使细胞能够在ER应激中存活。这种高度协调的反应对于应激和正常条件下ER产生的所有蛋白质的折叠、加工、输出和降解至关重要。需要未折叠蛋白反应（UPR）的生理条件的实例包括浆细胞分化（1）和胰腺炎细胞功能（2）。肿瘤细胞对缺氧条件和葡萄糖剥夺的适应也诱导了ER应激反应（3）。此外，越来越多的证据表明，在神经变性疾病如亨廷顿氏病、阿尔茨海默氏病和朊病毒相关疾病中存在蛋白质错误折叠（4）。在感应未折叠蛋白质时，IRE 1寡聚化，通过自磷酸化激活，并利用其内切核糖核酸酶活性从酵母或其哺乳动物同源物XBP-1中的转录因子Hac 1 p切除内含子，XBP-1是我们实验室首次分离的一种环状AMP反应元件结合蛋白/激活转录因子家族成员（5）。这种非常规mRNA剪接事件导致无活性的267个氨基酸的未剪接XBP-1（XBP-1u）蛋白转化为有活性的371个氨基酸的剪接XBP-1（XBP-1 s）蛋白（6 - 8）。我们先前已经证明XBP-1对于高度分泌细胞的分化是必需的，包括胚胎肝细胞、外分泌胰腺腺泡细胞和浆细胞（1，9 - 11）。关于控制DC分化的因素已经了解了很多。fms相关酪氨酸激酶3配体（Flt 3L）（12，13）和GM-CSF（14，15）是DC发育的公知正调节剂。最近的一项研究描述了Toll样受体（TLR）刺激参与造血细胞增殖和随后的DC分化（16）。此外，几种影响体内单个DC亚群发育的细胞内信号分子和转录因子-包括Gfi 1、Id 2、Ikaros、IFN调节因子2（IRF-2）、IRF-4、IRF-8、relB、Runx 3、Spi-B和STAT 3-已被报道（17 - 24）。树突状细胞（Dendritic cells，DC）在免疫应答的启动、维持和消退中起关键作用。DC的存活受到细胞因子和Toll样受体（TLR）信号转导等细胞外刺激的严格控制，但将这些细胞外刺激转化为DC的生存或死亡的细胞内事件仍然知之甚少。内质网（ER）应激，或未折叠的蛋白质。
Signals emanating from the ER induce a tran-scriptional program that enables cells to survive ER stress. This highly coordinated response is essential for the folding, processing, export, and degradation of all proteins emanating from the ER during stressed and normal conditions. Examples of physiological conditions that require the unfolded protein response (UPR) include plasma cell diff erentiation (1) and pancreatic  cell function (2). Adaptation of tumor cells to hypoxic conditions and glucose deprivation also induces the ER stress response (3). Additionally , there is increasing evidence of protein misfolding in neurodegenerative diseases such as Huntington ' s, Alzheimer ' s, and prion-related diseases (4).The UPR exists in all eukaryotes and consists of multiple signaling pathways, the most conserved of which is mediated by IRE1. Upon sensing unfolded proteins, IRE1 oligo-merizes, is activated by autophosphorylation, and uses its endoribonuclease activity to excise an intron from the transcription factor Hac1p in yeast or its mammalian homologue, XBP-1, a cyclic-AMP response element binding protein/ activating transcription factor family member fi rst isolated in our laboratory (5). This uncon-ventional mRNA splicing event results in the conversion of the inactive 267 – amino-acid un-spliced XBP-1 (XBP-1u) protein to an active 371 – amino-acid spliced XBP-1 (XBP-1s) protein (6 – 8). We have previously shown that XBP-1 is essential for the diff erentiation of highly se-cretory cells, including embryonic hepatocytes, exocrine pancreatic acinar cells, and plasma cells (1, 9 – 11). Much has been learned about the factors that control DC diff erentiation. The fms-related tyrosine kinase 3 ligand (Flt3L) (12, 13) and GM-CSF (14, 15) are well known positive regulators of DC development. A more recent study described the involvement of Toll-like receptor (TLR) stimulation in hematopoietic cell proliferation and subsequent DC diff eren-tiation (16). Additionally, several intracellular signaling molecules and transcription factors — including Gfi 1, Id2, Ikaros, IFN regulatory factor 2 (IRF-2), IRF-4, IRF-8, relB, Runx3, Spi-B, and STAT3 — that aff ect the development of individual DC subsets in vivo have been reported (17 – 24). The control of DC survival Dendritic cells (DCs) play a critical role in the initiation, maintenance, and resolution of an immune response. DC survival is tightly controlled by extracellular stimuli such as cytokines and Toll-like receptor (TLR) signaling, but the intracellular events that translate such extracellular stimuli into life or death for the DC remain poorly understood. The endoplas-mic reticulum (ER) stress, or unfolded protein …