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The NK cell receptor NKp46 recognizes ecto-calreticulin on ER-stressed cells.
- Source :
-
Nature [Nature] 2023 Apr; Vol. 616 (7956), pp. 348-356. Date of Electronic Publication: 2023 Apr 05. - Publication Year :
- 2023
-
Abstract
- Natural killer (NK) cell kill infected, transformed and stressed cells when an activating NK cell receptor is triggered <superscript>1</superscript> . Most NK cells and some innate lymphoid cells express the activating receptor NKp46, encoded by NCR1, the most evolutionarily ancient NK cell receptor <superscript>2,3</superscript> . Blockage of NKp46 inhibits NK killing of many cancer targets <superscript>4</superscript> . Although a few infectious NKp46 ligands have been identified, the endogenous NKp46 cell surface ligand is unknown. Here we show that NKp46 recognizes externalized calreticulin (ecto-CRT), which translocates from the endoplasmic reticulum (ER) to the cell membrane during ER stress. ER stress and ecto-CRT are hallmarks of chemotherapy-induced immunogenic cell death <superscript>5,6</superscript> , flavivirus infection and senescence. NKp46 recognition of the P domain of ecto-CRT triggers NK cell signalling and NKp46 caps with ecto-CRT in NK immune synapses. NKp46-mediated killing is inhibited by knockout or knockdown of CALR, the gene encoding CRT, or CRT antibodies, and is enhanced by ectopic expression of glycosylphosphatidylinositol-anchored CRT. NCR1)-deficient human (and Nrc1-deficient mouse) NK cells are impaired in the killing of ZIKV-infected, ER-stressed and senescent cells and ecto-CRT-expressing cancer cells. Importantly, NKp46 recognition of ecto-CRT controls mouse B16 melanoma and RAS-driven lung cancers and enhances tumour-infiltrating NK cell degranulation and cytokine secretion. Thus, NKp46 recognition of ecto-CRT as a danger-associated molecular pattern eliminates ER-stressed cells.<br /> (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
- Subjects :
- Animals
Humans
Mice
Alarmins metabolism
Cell Membrane metabolism
Endoplasmic Reticulum metabolism
Immunity, Innate
Immunological Synapses
Lung Neoplasms metabolism
Melanoma, Experimental metabolism
Zika Virus physiology
Calreticulin immunology
Calreticulin metabolism
Endoplasmic Reticulum Stress
Killer Cells, Natural metabolism
Natural Cytotoxicity Triggering Receptor 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 616
- Issue :
- 7956
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 37020026
- Full Text :
- https://doi.org/10.1038/s41586-023-05912-0