Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
Sci Signal. 2010 Feb 23;3(110):ra14. doi: 10.1126/scisignal.2000467.
Endosomes are emerging as specialized signaling compartments that endow receptors with distinct signaling properties. The diversity of endosomal signaling pathways and their contribution to various biological responses is still unclear. CD158d, which is also known as the killer cell immunoglobulin-like receptor (KIR) 2DL4 (KIR2DL4), is an endosome-resident receptor in natural killer (NK) cells that stimulates the release of a unique set of proinflammatory and proangiogenic mediators in response to soluble human leukocyte antigen G (HLA-G). Here, we identified the CD158d signaling cascade. In response to soluble agonist antibody or soluble HLA-G, signaling by CD158d was dependent on the activation of nuclear factor kappaB (NF-kappaB) and the serine-threonine kinase Akt. CD158d associated with the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), promoted the recruitment of Akt to endosomes, and stimulated the DNA-PKcs-dependent phosphorylation of Akt. The sequential requirement for DNA-PKcs, Akt, and NF-kappaB in signaling by CD158d delineates a previously uncharacterized endosomal signaling pathway for a proinflammatory response in NK cells.
内体正在成为具有特殊信号功能的特化信号隔室，为受体赋予独特的信号特性。内体信号通路的多样性及其对各种生物学反应的贡献尚不清楚。CD158d，也称为杀伤细胞免疫球蛋白样受体（KIR）2DL4（KIR2DL4），是自然杀伤（NK）细胞中内体驻留受体，可刺激可溶性人类白细胞抗原 G（HLA-G）响应释放一组独特的促炎和促血管生成介质。在这里，我们确定了 CD158d 信号级联。响应可溶性激动剂抗体或可溶性 HLA-G，CD158d 的信号传导依赖于核因子 kappaB（NF-kappaB）和丝氨酸-苏氨酸激酶 Akt 的激活。CD158d 与 DNA 依赖性蛋白激酶（DNA-PKcs）的催化亚基结合，促进 Akt 向内体的募集，并刺激 DNA-PKcs 依赖性 Akt 磷酸化。CD158d 信号传导中 DNA-PKcs、Akt 和 NF-kappaB 的顺序要求描绘了 NK 细胞中促炎反应的先前未表征的内体信号通路。
