Phosphorylation of the CARMA1 linker controls NF-κB activation
Phosphorylation of the CARMA1 linker controls NF-κB activation
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DOI：
10.1016/j.immuni.2005.09.014
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发表时间：
2005-12-01
期刊：
影响因子：
32.4
通讯作者：
Rawlings, DJ
中科院分区：
文献类型：
--
作者：
Sommer, K;Guo, BC;Rawlings, DJ
PKC亚型和CARMA 1在免疫受体依赖性NF-κ B活化中起关键作用。我们测试了CARMA 1的PKC依赖性磷酸化是否直接调节这种信号级联。B细胞抗原受体（BCR）结合导致CARMA 1逐步募集到脂筏中，并导致CARMA 1与PKC β结合和磷酸化。此外，PKC β与富含丝氨酸的CARMA 1接头相互作用，PKC β和PKC 0均磷酸化该接头内相同的丝氨酸残基（S564、S649和S657）。其中两个位点的突变消除了CARMA 1的功能活性。相反，接头的缺失导致组成型、受体和PKC非依赖性NF-κ B活化。总之，我们的数据支持CARMA 1磷酸化通过触发从非活性到活性CARMA 1构象异构体的转变来控制NF-κ B活化的模型。这种PKC依赖性开关调节CARD和CC结构域的可及性，并控制膜相关licS激酶（IKK）信号体的组装和完全激活。
PKC isoforms and CARMA1 play crucial roles in immunoreceptor-dependent NF-KB activation. We tested whether PKC-dependent phosphorylation of CARMA1 directly regulates this signaling cascade. B cell antigen receptor (BCR) engagement led to the progressive recruitment of CARMA1 into lipid rafts and to the association of CARMA1 with, and phosphorylation by, PKC beta. Furthermore, PKC beta interacted with the serinerich CARMA1 linker, and both PKC beta and PKC0 phosphorylated identical serine residues (S564, S649, and S657) within this linker. Mutation of two of these sites ablated the functional activity of CARMA1. In contrast, deletion of the linker resulted in constitutive, receptor and PKC-independent NF-KB activation. Together, our data support a model whereby CARMA1 phosphorylation controls NF-KB activation by triggering a shift from an inactive to an active CARMA1 conformer. This PKC-dependent switch regulates accessibility of the CARD and CC domains and controls assembly and full activation of the membrane-associated licS kinase (IKK) signalosome.