Research ArticleImmunology

Ubiquitin-dependent endocytosis of NKG2D-DAP10 receptor complexes activates signaling and functions in human NK cells

Sci. Signal.  27 Oct 2015:
Vol. 8, Issue 400, pp. ra108
DOI: 10.1126/scisignal.aab2724

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Turning on natural killer cells

Ligands present on the surface of tumor cells stimulate and activate natural killer (NK) cells of the innate immune system, which then trigger tumor cell death. Quatrini et al. found that the ligand-dependent internalization of a complex containing the stimulatory receptor NKG2D and the adaptor protein DAP10 depended on DAP10 ubiquitylation. Internalized receptor complexes in endosomes stimulated signaling by the kinase ERK, which was required for the secretion of cytolytic granules. Mutation of DAP10 to prevent its ubiquitylation resulted in decreased receptor internalization and defective cytotoxic responses, indicating that internalized receptors stimulate NK cell functions.

Abstract

Cytotoxic lymphocytes share the presence of the activating receptor NK receptor group 2, member D (NKG2D) and the signaling-competent adaptor DNAX-activating protein 10 (DAP10), which together play an important role in antitumor immune surveillance. Ligand stimulation induces the internalization of NKG2D-DAP10 complexes and their delivery to lysosomes for degradation. In experiments with human NK cells and cell lines, we found that the ligand-induced endocytosis of NKG2D-DAP10 depended on the ubiquitylation of DAP10, which was also required for degradation of the internalized complexes. Moreover, through combined biochemical and microscopic analyses, we showed that ubiquitin-dependent receptor endocytosis was required for the activation of extracellular signal–regulated kinase (ERK) and NK cell functions, such as the secretion of cytotoxic granules and the inflammatory cytokine interferon-γ. These results suggest that NKG2D-DAP10 endocytosis represents a means to decrease cell surface receptor abundance, as well as to control signaling outcome in cytotoxic lymphocytes.

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