Transcription elongation factor ELL2 drives Ig secretory-specific mRNA production and the unfolded protein response.
Transcription elongation factor ELL2 drives Ig secretory-specific mRNA production and the unfolded protein response.
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DOI：
10.4049/jimmunol.1401608
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发表时间：
2014-11-01
期刊：
影响因子：
--
通讯作者：
Milcarek C
中科院分区：
文献类型：
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作者：
Park KS;Bayles I;Szlachta-McGinn A;Paul J;Boiko J;Santos P;Liu J;Wang Z;Borghesi L;Milcarek C
B细胞分化为抗体分泌细胞诱导基因转录、Igh RNA加工、未折叠蛋白反应和细胞结构的变化。转录延伸因子ELL 2（119个富含赖氨酸的白血病基因）刺激来自重链基因的Igh mRNA的分泌形式的加工。构建在外显子1或外显子3中具有ELL 2基因floxed的小鼠（小家鼠），并与CD 19驱动的cre/CD 19+杂交。B细胞特异性ELL 2条件性敲除（ell 2loxp/loxp CD 19 cre/+）在NP-ficoll和NP-KLH免疫的动物中均表现出减少的体液应答;回忆应答也减少。相对于对照动物，条件性基因敲除中骨髓中未成熟和再循环的B细胞数量增加，而脾脏中的浆细胞减少。在条件性基因敲除的骨髓中有较少的IgG 1抗体产生细胞。来自ELL 2缺陷型小鼠脾的LPS离体刺激的B220 loCD 138+细胞的丰度比来自对照脾B细胞的丰度低4倍，具有分泌的Igh的缺乏和膨胀的异常表现的ER。在ELL 2缺陷细胞中，IRE 1 α被有效磷酸化，但未剪接和剪接的IG κ、ATF 6、BiP、细胞周期蛋白B2、OcaB（BOB 1、Pou 2af 1）和XBP 1 mRNA的量严重减少。ELL 2增强BCMA的表达，这对长期存活很重要。细胞周期蛋白B2和典型的UPR启动子元件的转录产量被ELL 2 cDNA上调。因此，ELL 2对于抗体分泌、XBP 1表达和未折叠蛋白应答的许多方面都很重要。
Differentiation of B cells into antibody secreting cells induces changes in gene transcription, Igh RNA processing, the unfolded protein response, and cell architecture. The transcription elongation factor ELL2 (eleven nineteen lysine-rich leukemia gene) stimulates the processing of the secreted form of the Igh mRNA from the heavy chain gene. Mice (mus musculus) with the ELL2 gene floxed in either exon 1 or exon 3 were constructed and crossed to CD19 driven cre/ CD19+. The B-cell specific ELL2 conditional knockouts (ell2loxp/loxp CD19cre/+) exhibit curtailed humoral responses both in NP-ficoll and NP-KLH immunized animals; recall responses were also diminished. The number of immature and recirculating B cells in the bone marrow is increased in the conditional knockouts while plasma cells in spleen are reduced relative to control animals. There are fewer IgG1 antibody producing cells in the bone marrow of conditional knockouts. LPS ex vivo stimulated B220loCD138+ cells from ELL2 deficient mouse spleens are 4-fold less abundant than from control splenic B-cells, have a paucity of secreted Igh, and distended, abnormal appearing ER. IRE1alpha is efficiently phosphorylated but the amounts of Ig kappa, ATF6, BiP, Cyclin B2, OcaB (BOB1, Pou2af1), and XBP1 mRNAs, unspliced and spliced, are severely reduced in ELL2 deficient cells. ELL2 enhances the expression of BCMA, important for long term survival. Transcription yields from the cyclin B2 and the canonical UPR promoter elements are up-regulated by ELL2 cDNA. Thus ELL2 is important for many aspects of antibody secretion, XBP1 expression, and the unfolded protein response.