Regulation of B cell homeostasis and activation by the tumor suppressor gene CYLD.
Regulation of B cell homeostasis and activation by the tumor suppressor gene CYLD.
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DOI：
10.1084/jem.20070318
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发表时间：
2007-10-29
期刊：
影响因子：
--
通讯作者：
Waisman A
中科院分区：
文献类型：
--
作者：
Hövelmeyer N;Wunderlich FT;Massoumi R;Jakobsen CG;Song J;Wörns MA;Merkwirth C;Kovalenko A;Aumailley M;Strand D;Brüning JC;Galle PR;Wallach D;Fässler R;Waisman A
B细胞稳态受多种信号传导过程调节，包括核因子-κB（NF-κB）、BAFF-和B细胞受体信号传导。有条件地破坏参与这些途径的基因，揭示了从细胞表面到细胞核的信号传导机制。我们描述了一种新的小鼠品系，其仅过量表达CYLD的天然剪接变体（CYLDex 7/8小鼠），CYLD是NF-κB信号传导不可或缺的去泛素化酶。这种较短的CYLD蛋白缺乏全长CYLD中存在的TRAF 2和NEMO结合位点。在所有外周淋巴器官中，成熟B淋巴细胞群体急剧扩增。B淋巴细胞本身表现出延长的存活期，并表现出在CYLD完全缺失的小鼠中不发生的各种信号紊乱。虽然全长和突变CYLD都能够与Bcl-3相互作用，但Bcl-3的主要核积累发生在CYLD突变B细胞中。然而，更引人注目的是NF-κB蛋白p100和RelB在CYLDex 7/8 B细胞中的积累，其可能与核Bcl-3结合，导致Bcl-2表达水平增加。这些结果表明，CYLD可以积极和消极调节信号转导和体内B细胞的稳态，这取决于CYLD剪接变异体的表达。
B cell homeostasis is regulated by multiple signaling processes, including nuclear factor-κB (NF-κB), BAFF-, and B cell receptor signaling. Conditional disruption of genes involved in these pathways has shed light on the mechanisms governing signaling from the cell surface to the nucleus. We describe a novel mouse strain that expresses solely and excessively a naturally occurring splice variant of CYLD (CYLDex7/8 mice), which is a deubiquitinating enzyme that is integral to NF-κB signaling. This shorter CYLD protein lacks the TRAF2 and NEMO binding sites present in full-length CYLD. A dramatic expansion of mature B lymphocyte populations in all peripheral lymphoid organs occurs in this strain. The B lymphocytes themselves exhibit prolonged survival and manifest a variety of signaling disarrangements that do not occur in mice with a complete deletion of CYLD. Although both the full-length and the mutant CYLD are able to interact with Bcl-3, a predominant nuclear accumulation of Bcl-3 occurs in the CYLD mutant B cells. More dramatic, however, is the accumulation of the NF-κB proteins p100 and RelB in CYLDex7/8 B cells, which, presumably in combination with nuclear Bcl-3, results in increased levels of Bcl-2 expression. These findings suggest that CYLD can both positively and negatively regulate signal transduction and homeostasis of B cells in vivo, depending on the expression of CYLD splice variants.
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影响因子：
64.8
作者：
RICKERT, RC;RAJEWSKY, K;ROES, J
通讯作者：
ROES, J
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64.8
作者：
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通讯作者：
Mosialos, G