Department of Molecular Immunology, Research Institute for Microbial Diseases, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Proc Natl Acad Sci U S A. 2012 Dec 18;109(51):21022-7. doi: 10.1073/pnas.1218925110. Epub 2012 Dec 5.
Germinal centers (GCs) are specialized microenvironments in secondary lymphoid organs where high-affinity antibody-producing B cells are selected based on B-cell antigen receptor (BCR) signal strength. BCR signaling required for normal GC selection is uncertain. We have found that protein kinase N1 (PKN1, also known as PRK1) negatively regulates Akt kinase downstream of the BCR and that this regulation is necessary for normal GC development. PKN1 interacted with and inhibited Akt1 kinase and transforming activities. Pkn1(-/-) B cells were hyperresponsive and had increased phosphorylated Akt1 levels upon BCR stimulation. In the absence of immunization or infection, Pkn1(-/-) mice spontaneously formed GCs and developed an autoimmune-like disease with age, which was characterized by autoantibody production and glomerulonephritis. More B cells, with fewer somatic BCR gene V region hypermutations were selected in Pkn1(-/-) GCs. These results indicate that PKN1 down-regulation of BCR-activated Akt activity is critical for normal GC B-cell survival and selection.
生发中心（GCs）是次级淋巴器官中的特化微环境，其中高亲和力的抗体产生 B 细胞根据 B 细胞抗原受体（BCR）信号强度进行选择。BCR 信号对于正常 GC 选择是不确定的。我们发现蛋白激酶 N1（PKN1，也称为 PRK1）负调控 BCR 下游的 Akt 激酶，这种调控对于正常 GC 发育是必需的。PKN1 与 Akt1 激酶相互作用并抑制其活性。PKN1(-/-) B 细胞对外界刺激过度反应，BCR 刺激后其磷酸化 Akt1 水平升高。在没有免疫接种或感染的情况下，Pkn1(-/-) 小鼠自发形成 GC 并随年龄增长发展出自免疫样疾病，其特征是产生自身抗体和肾小球肾炎。在 Pkn1(-/-) GCs 中，更多的 B 细胞被选择，这些 B 细胞的体细胞 BCR 基因 V 区超突变较少。这些结果表明，PKN1 下调 BCR 激活的 Akt 活性对于正常 GC B 细胞的存活和选择至关重要。
