Deletion of cIAP1 and cIAP2 in murine B lymphocytes constitutively activates cell survival pathways and inactivates the germinal center response
Deletion of cIAP1 and cIAP2 in murine B lymphocytes constitutively activates cell survival pathways and inactivates the germinal center response
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DOI：
10.1182/blood-2010-10-312793
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发表时间：
2011-04-14
期刊：
影响因子：
20.3
通讯作者：
Brink, Robert
中科院分区：
文献类型：
--
作者：
Gardam, Sandra;Turner, Vivian M.;Brink, Robert
B细胞需要通过TNF家族受体的B细胞活化因子（BAFF-R）和CD 40递送的信号以在体内存活并产生抗体应答。体外数据表明，这些信号是由同源环指蛋白cIAP 1和cIAP 2，与TRAF 2和TRAF 3合作控制的。也有越来越多的证据表明，所有4个这些信号分子可以作为肿瘤抑制剂在人类B系恶性肿瘤。然而，由于缺乏适当的体内模型，还不可能确定cIAP 1和cIAP 2在控制B细胞生理学中的作用。在这里，我们描述了一个独特的转基因小鼠，其中连接cIap 1和cIap 2基因可以独立失活。cIAP 1和cIAP 2的缺失（但不是单独的蛋白质）使原代B细胞的存活不依赖于BAFF-R，并导致其在体内不受控制的积累。缺乏cIAP 1和cIAP 2的B细胞也不能形成生发中心，这是抗体介导免疫的关键步骤。这些数据定义了cIAP 1/cIAP 2在调节B细胞存活和反应性中的基本作用，表明这需要与TRAF 2直接结合，并表明TRAF 2，TRAF 3和cIAP 1/cIAP 2的突变如何导致B系恶性肿瘤，如多发性骨髓瘤。（血。2011;117（15）：4041-4051）
B cells require signals delivered through B-cell activating factor of the TNF family receptor (BAFF-R) and CD40 to survive and produce antibody responses in vivo. In vitro data indicate that these signals are controlled by the homologous RING finger proteins cIAP1 and cIAP2, in collaboration with TRAF2 and TRAF3. There is also mounting evidence that all 4 of these signaling molecules can act as tumor suppressors in human B-lineage malignancies. However, it has not been possible to identify the roles of cIAP1 and cIAP2 in controlling B-cell physiology because of the absence of an appropriate in vivo model. Here we describe a unique genetically modified mouse in which the linked cIap1 and cIap2 genes can be independently inactivated. Deletion of cIAP1 plus cIAP2 (but not either protein alone) rendered primary B cells independent of BAFF-R for their survival and led to their uncontrolled accumulation in vivo. B cells deficient in cIAP1 and cIAP2 were also incapable of forming germinal centers, a key step in antibody-mediated immunity. These data define a fundamental role for cIAP1/cIAP2 in regulating B-cell survival and responsiveness, show this requires direct binding to TRAF2, and suggest how mutations of TRAF2, TRAF3, and cIAP1/cIAP2 contribute to B-lineage malignancies, such as multiple myeloma. (Blood. 2011;117(15):4041-4051)