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

Abstract

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 is an endosome-resident, killer cell Ig-like receptor (KIR2DL4) in natural killer cells that stimulates release of a unique set of pro-inflammatory and pro-angiogenic mediators in response to soluble HLA-G. We identify here the CD158d signaling cascade. In response to soluble agonist antibody or soluble HLA-G, signaling by CD158d was dependent on activation of NF-κB and Akt. CD158d associated with DNA-PKcs, promoted Akt recruitment to endosomes, and induced DNA-PKcs-dependent Akt phosphorylation. The sequential requirement for DNA-PKcs, Akt, and NF-κB in signaling by receptor CD158d delineates a new endosomal signaling pathway for a pro-inflammatory response.

Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling

“…DDR signaling is mediated primarily by proteins of the phosphoinositide 3-kinase-like kinase family, including ATM, ATR, and DNA-PK, to coordinate cellular responses such as survival, apoptosis, or senescence of damaged cells (12). Phosphorylation of Akt at Ser-473 by DNA-PKcs was implicated in signaling by CD158d in NK cells (11). DNA-PKcs also activates Akt during ionizing radiation-induced DDR, leading to the up-regulation of the cyclin-dependent kinase inhibitor p21 (also known as Cip1 or Waf1) (13).…”

“…In contrast, CD158d resides in early endosomes. On endocytosis of either soluble HLA-G or agonist antibody, CD158d initiates a signaling pathway through the serine/ threonine kinases DNA-PKcs and Akt, and NF-κB (7,11). We set out to study why endosomal signaling by CD158d uses a kinase involved in DNA repair to produce a proinflammatory and proangiogenic response.…”

HLA-G-mediated NK cell senescence promotes vascular remodeling: implications for reproduction

“…38 Signaling by KIR2DL4 is distinct from that of other KIR as it is independent of both ITIM and ITAM-mediated signaling and resistant to inhibitors of Src family kinases and phosphatidylinositide 3-kinase. 49 Unexpectedly, Akt phosphorylation (at serine 473) was identified by kinase phosphorylation-profiling upon activation through KIR2DL4. Importantly, this Akt activation upon KIR2DL4 engagement required its endocytosis.…”

“…This approach identified DNA-PKcs, a DNA damage signaling kinase, as the kinase responsible for phosphorylation of Akt at serine 473. 49 KIR2DL4 has a conserved binding motif in its cytoplasmic tail for the ubiquitin ligase TNF-receptor-associated factor 6. Its association with TNF-receptor-associated factor 6 results in phosphorylation of the kinase TAK1 and links it to nuclear factor kappa B activation pathways.…”

The HLA-G cycle provides for both NK tolerance and immunity at the maternal–fetal interface

“…Soluble HLA-G has been shown to bind KIR2DL4 on peripheral blood NK cells (pNK) and, upon binding, the KIR2DL4-HLA-G complex internalizes and signaling occurs from an endosomal compartment (18,21). The fact that signaling from the KIR2DL4-HLA-G complex preferentially occurs from the endosomal compartment indicates that HLA-G may play a greater role than simply protecting HLA-G+ cells from NK cytotoxicity.…”