B Lymphocyte-Specific Loss of Ric-8A Results in a Gα Protein Deficit and Severe Humoral Immunodeficiency.
B Lymphocyte-Specific Loss of Ric-8A Results in a Gα Protein Deficit and Severe Humoral Immunodeficiency.
复制标题
DOI：
10.4049/jimmunol.1500523
复制
发表时间：
2015-09-01
期刊：
影响因子：
--
通讯作者：
Kehrl JH
中科院分区：
文献类型：
--
作者：
Boularan C;Hwang IY;Kamenyeva O;Park C;Harrison K;Huang Z;Kehrl JH
抗胆碱酯酶抑制剂8A（Ric-8A）是一种高度进化保守的胞浆蛋白，最初在C. elegans，在那里它被指定在不对称细胞分裂中起调节作用。作为Gαi、Gαq和Gα12/13的鸟嘌呤核苷酸交换因子，以及作为胚胎干细胞系中新生Gα亚基与细胞膜初始结合所需的分子伴侣。为了检测其在造血和B淋巴细胞中的作用，我们产生了ric 8 fl/flvav 1-cre和ric 8 fl/flmb 1-cre小鼠。主要造血细胞谱系在ric 8 fl/flvav 1-cre小鼠中发育，尽管Gαi2/3、Gαq和Gα13蛋白严重减少。Ric-8A的B淋巴细胞特异性丧失不损害骨髓B淋巴细胞生成，但脾边缘区B细胞发育失败，并且B细胞缺乏淋巴器官。ric 8 fl/flmb 1-cre B细胞在B细胞分化过程中表现出对趋化因子的不良反应、异常运输、不适当的原位定位和极性成分的丢失。ric 8 fl/flmb 1-cre小鼠的淋巴结构严重受损，一级和二级抗体反应较差。在B淋巴细胞中，Ric-8A对正常Gα蛋白水平至关重要;并且是B细胞分化、运输和抗体应答所必需的。
Resistance to inhibitors of cholinesterase 8A (Ric-8A) is a highly evolutionarily conserved cytosolic protein initially identified in C. elegans, where it was assigned a regulatory role in asymmetric cell divisions. It functions as a guanine nucleotide exchange factor for Gαi, Gαq, and Gα12/13 and as a molecular chaperone required for the initial association of nascent Gα subunits with cellular membranes in embryonic stem cell lines. To test its role in hematopoiesis and B lymphocytes specifically, we generated ric8fl/flvav1-cre and ric8fl/flmb1-cre mice. The major hematopoietic cell lineages developed in the ric8fl/flvav1-cre mice, notwithstanding severe reduction in Gαi2/3, Gαq, and Gα13 proteins. B lymphocyte specific loss of Ric-8A did not compromise bone marrow B lymphopoiesis, but splenic marginal zone B cell development failed, and B cells underpopulated lymphoid organs. The ric8fl/flmb1-cre B cells exhibited poor responses to chemokines, abnormal trafficking, improper in situ positioning, and loss of polarity components during B cell differentiation. The ric8fl/flmb1-cre mice had a severely disrupted lymphoid architecture and poor primary and secondary antibody responses. In B lymphocytes, Ric-8A is essential for normal Gα protein levels; and is required for B cell differentiation, trafficking, and antibody responses.