Research ArticleCell Biology

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

Science Signaling  23 Feb 2010:
Vol. 3, Issue 110, pp. ra14
DOI: 10.1126/scisignal.2000467

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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.