DNA-PKcs Controls an Endosomal Signaling Pathway for a Proinflammatory Response by Natural Killer Cells

DNA-dependent protein kinase and Akt are required for the activation of NF-κB by an endosomal receptor. Under the Surface In addition to serving as compartments in which signaling by internalized receptors is terminated, endosomes provide venues in which other receptors continue to signal or even trigger alternative pathways. Indeed, some receptors that fail to signal at the membrane function efficiently in endosomes. CD158d, an endosome-resident, immunoglobulin-like receptor found mostly in natural killer (NK) cells, triggers a proinflammatory and proangiogenic pathway in response to soluble human leukocyte antigen G (HLA-G). Uptake of fetal trophoblast–derived HLA-G by maternal NK cells may trigger the vascular remodeling required to establish an effective blood supply to the fetus, but how CD158d stimulates this response is unclear. Rajagopalan et al. found that endosomal CD158d activated nuclear factor κB (NF-κB) through a mechanism that depended on the kinase Akt, but not phosphatidylinositol 3-kinase (PI3K). In addition, CD158d associated with the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), which phosphorylated Akt at the endosome. In addition to expanding the known roles of DNA-PKcs, this study also highlights a PI3K-independent, endosomal function for Akt that is required for a proinflammatory response in NK cells. 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 κB (NF-κB) 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-κB in signaling by CD158d delineates a previously uncharacterized endosomal signaling pathway for a proinflammatory response in NK cells.