CARMA1连接区的磷酸化调控核因子-κB的激活。

Phosphorylation of the CARMA1 linker controls NF-kappaB activation.

作者信息

Sommer Karen, Guo Beichu, Pomerantz Joel L, Bandaranayake Ashok D, Moreno-García Miguel E, Ovechkina Yulia L, Rawlings David J

机构信息

Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington 98195, USA.

出版信息

Immunity. 2005 Dec;23(6):561-74. doi: 10.1016/j.immuni.2005.09.014.

DOI:10.1016/j.immuni.2005.09.014

PMID:16356855

Abstract

PKC isoforms and CARMA1 play crucial roles in immunoreceptor-dependent NF-kappaB 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, PKCbeta. Furthermore, PKCbeta interacted with the serine-rich CARMA1 linker, and both PKCbeta and PKCtheta 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-kappaB activation. Together, our data support a model whereby CARMA1 phosphorylation controls NF-kappaB 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 IkappaB kinase (IKK) signalosome.

摘要

蛋白激酶C（PKC）同工型和CARD11在免疫受体依赖性核因子κB（NF-κB）激活中发挥关键作用。我们测试了CARD11的PKC依赖性磷酸化是否直接调节这一信号级联反应。B细胞抗原受体（BCR）的结合导致CARD11逐渐募集到脂筏中，并导致CARD11与PKCβ结合并被其磷酸化。此外，PKCβ与富含丝氨酸的CARD11连接区相互作用，PKCβ和PKCθ都使该连接区内相同的丝氨酸残基（S564、S649和S657）磷酸化。其中两个位点的突变消除了CARD11的功能活性。相反，连接区的缺失导致组成性的、不依赖受体和PKC的NF-κB激活。总之，我们的数据支持一种模型，即CARD11磷酸化通过触发从无活性到有活性的CARD11构象转变来控制NF-κB激活。这种PKC依赖性开关调节CARD和卷曲螺旋（CC）结构域的可及性，并控制膜相关的核因子κB抑制蛋白激酶（IKK）信号小体的组装和完全激活。