The BiP cochaperone ERdj4 is required for B cell development and function.
The BiP cochaperone ERdj4 is required for B cell development and function.
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DOI：
10.1371/journal.pone.0107473
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Weaver TE
中科院分区：
文献类型：
--
作者：
Fritz JM;Weaver TE
ERdj4 是一种 BiP 共伴侣蛋白，受未折叠蛋白反应调节，促进内质网中未折叠和/或错误折叠蛋白的降解。由于未折叠蛋白反应在 B 细胞成熟和抗体产生中发挥着关键作用，因此培育了 ERdj4 基因捕获小鼠来确定 B 细胞稳态是否需要该伴侣。捕获等位基因的纯合性导致骨髓细胞中 ERdj4 的低效表达以及骨髓中造血谱系的异常发育。与对照组相比，ERdj4基因捕获小鼠的骨髓细胞数量增加，而红细胞和B淋巴细胞数量减少。发现了一种内在的 B 细胞缺陷，该缺陷会降低 B 细胞前体（包括大和小前 B 细胞和未成熟 B 细胞）的存活率。与 B 淋巴细胞生成受损一致，ERdj4 基因捕获小鼠的骨髓和脾脏中成熟滤泡 B 细胞的数量均减少。矛盾的是，未受到攻击的 ERdj4 基因陷阱小鼠表现出非特异性高丙种球蛋白血症，而基因陷阱 B 细胞响应 LPS 刺激而表现出增殖、存活和同种型转换增加。尽管ERdj4基因捕获小鼠对T细胞非依赖性抗原有正常反应，但它们未能在体内对T细胞依赖性抗原产生特异性抗体反应。总的来说，这些发现表明 ERdj4 的伴侣活性是 B 细胞祖细胞的存活和正常抗体产生所必需的。
ERdj4 is a BiP cochaperone regulated by the unfolded protein response to facilitate degradation of unfolded and/or misfolded proteins in the endoplasmic reticulum. As the unfolded protein response plays a critical role in B cell maturation and antibody production, ERdj4 gene trap mice were generated to determine if this chaperone was required for B cell homeostasis. Homozygosity for the trapped allele resulted in hypomorphic expression of ERdj4 in bone marrow cells and abnormal development of hematopoietic lineages in the bone marrow. The number of myeloid cells was increased, while the number of erythroid and B lymphoid cells was reduced in ERdj4 gene trap mice compared to controls. An intrinsic B cell defect was identified that decreased survival of B cell precursors including large and small pre-B, and immature B cells. Consistent with impaired B lymphopoiesis, the number of mature follicular B cells was reduced in both the bone marrow and spleen of ERdj4 gene trap mice. Paradoxically, unchallenged ERdj4 gene trap mice showed non-specific hypergammaglobulinemia and gene trap B cells exhibited increased proliferation, survival and isotype switching in response to LPS stimulation. Although ERdj4 gene trap mice responded normally to T cell-independent antigen, they failed to mount a specific antibody response to T cell-dependent antigen in vivo. Collectively, these findings demonstrate that the chaperone activity of ERdj4 is required for survival of B cell progenitors and normal antibody production.
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DOI：
10.1084/jem.20120994
发表时间：
2012-07-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ma CS;Deenick EK;Batten M;Tangye SG
通讯作者：
Tangye SG
影响因子：
20.3
作者：
Cariappa, Annaiah;Chase, Catharine;Pillai, Shiv
通讯作者：
Pillai, Shiv
影响因子：
64.8
作者：
Reimold, AM;Iwakoshi, NN;Glimcher, LH
通讯作者：
Glimcher, LH
影响因子：
21.3
作者：
Randow, F;Seed, B
通讯作者：
Seed, B
影响因子：
20.3
作者：
Lindsley, Robert Coleman;Thomas, Matthew;Allman, David
通讯作者：
Allman, David