Expression of ligands for the NKG2D activating receptor are linked to proliferative signals (108.2)

Abstract NKG2D is an activating receptor expressed on NK cells, CD8 T cells, and portions of NKT cells, gd T cells and CD4 T cells. The ligands for NKG2D receptor are surprisingly diverse, and emerging evidence suggests that different ligands are regulated by distinct cellular stress pathways, and in some cases a specific ligand is regulated by a several stress pathways acting in concert. In this study, we have identified a novel mechanism of regulation of a Rae1 family NKG2D ligand by proliferation stress. In proliferating B6 fibroblasts, Rae1e is induced at both the mRNA and protein levels, and in a manner that is not dependent on the DNA damage response or oxidative stress. Induction and maintenance of Rae1 expression is inhibited by growth factor starvation or any of numerous inhibitors of cell proliferation. Run-on transcription assays demonstrated that regulation is at the level of transcription. Ongoing studies suggest the role of specific cell cycle regulators as essential for Rae1 expression, and have probed their role in this process. This pathway implicates proliferation stress that occurs early in tumorigenesis and infections as a danger signal that induces the innate immune response.