The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors
The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors
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DOI：
10.1038/ni1466
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发表时间：
2007-06-01
影响因子：
30.5
通讯作者：
Saito, Takashi
中科院分区：
文献类型：
--
作者：
Hara, Hiromitsu;Ishihara, Chitose;Saito, Takashi
基于免疫受体酪氨酸的激活基序（ITAM）在获得性免疫中的抗原受体信号传导中是至关重要的。虽然与骨髓细胞上的ITAM-承载衔接子FcRc和DAP 12相关的受体已被提出激活先天免疫应答，但将这些受体与“下游”信号传导事件偶联的机制尚不清楚。CARMA 1-Bcl-10-MALT 1复合物对于淋巴细胞中转录因子NF-κ B的活化至关重要，但在骨髓细胞中的功能尚不清楚。在这里，我们报告说，基因编码Bcl-10接头结合伴侣CARD 9的缺失导致受损的骨髓细胞激活NF-κ B B信号通过几个ITAM相关受体。此外，CARD 9是Toll样受体通过激活丝裂原活化蛋白激酶诱导的树突状细胞活化所必需的。尽管Bcl 10（-/-）和Card 9（-/-）小鼠在骨髓细胞中具有相似的信号传导障碍，但Card 11（-/-）（CARMA 1缺陷型）骨髓细胞反应是正常的，尽管Card 11（-/-）淋巴细胞在抗原受体介导的活化中有缺陷，但Card 9（-/-）淋巴细胞没有。因此，通过ITAM相关受体或Toll样受体的淋巴细胞和骨髓细胞的活化分别由CARMA 1-Bcl-10和CARD 9-Bcl-10调节。
Immunoreceptor tyrosine-based activation motifs (ITAMs) are crucial in antigen receptor signaling in acquired immunity. Although receptors associated with the ITAM-bearing adaptors FcRc and DAP12 on myeloid cells have been suggested to activate innate immune responses, the mechanism coupling those receptors to 'downstream' signaling events is unclear. The CARMA1-Bcl-10-MALT1 complex is critical for the activation of transcription factor NF-kappa B in lymphocytes but has an unclear function in myeloid cells. Here we report that deletion of the gene encoding the Bcl-10 adaptor-binding partner CARD9 resulted in impaired myeloid cell activation of NF-kappa B signaling by several ITAM-associated receptors. Moreover, CARD9 was required for Toll-like receptor-induced activation of dendritic cells through the activation of mitogen-activated protein kinases. Although Bcl10(-/-) and Card9(-/-) mice had similar signaling impairment in myeloid cells, Card11(-/-) (CARMA1-deficient) myeloid cell responses were normal, and although Card11(-/-) lymphocytes were defective in antigen receptor-mediated activation, Card9(-/-) lymphocytes were not. Thus, the activation of lymphoid and myeloid cells through ITAM-associated receptors or Toll-like receptors is regulated by CARMA1-Bcl-10 and CARD9-Bcl-10, respectively.