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Disulphide-isomerase-enabled shedding of tumour-associated NKG2D ligands


Tumour-associated ligands of the activating NKG2D (natural killer group 2, member D; also called KLRK1) receptor—which are induced by genotoxic or cellular stress—trigger activation of natural killer cells and co-stimulation of effector T cells, and may thus promote resistance to cancer1,2,3,4,5,6. However, many progressing tumours in humans counter this anti-tumour activity by shedding the soluble major histocompatibility complex class-I-related ligand MICA, which induces internalization and degradation of NKG2D and stimulates population expansions of normally rare NKG2D+CD4+ T cells with negative regulatory functions7,8,9. Here we show that on the surface of tumour cells, MICA associates with endoplasmic reticulum protein 5 (ERp5; also called PDIA6 or P5), which, similar to protein disulphide isomerase, usually assists in the folding of nascent proteins inside cells10. Pharmacological inhibition of thioreductase activity and ERp5 gene silencing revealed that cell-surface ERp5 function is required for MICA shedding. ERp5 and membrane-anchored MICA form transitory mixed disulphide complexes from which soluble MICA is released after proteolytic cleavage near the cell membrane. Reduction of the seemingly inaccessible disulphide bond in the membrane-proximal α3 domain of MICA must involve a large conformational change that enables proteolytic cleavage. These results uncover a molecular mechanism whereby domain-specific deconstruction regulates MICA protein shedding, thereby promoting tumour immune evasion, and identify surface ERp5 as a strategic target for therapeutic intervention.

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Figure 1: Surface interactions of MICA with ERp5 and HSPA5.
Figure 2: Tumour-associated ERp5 surface expression and pharmacological inhibition of sMICA shedding.
Figure 3: ERp5 is required for sMICA shedding.
Figure 4: ERp5–MICA disulphide exchange enables MICA cleavage.
Figure 5: ERp5 exhibits specificity for the MICA α3 domain.

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We thank W. Carter for protein purification advice; M. Welcker for help with siRNA expression; W. Lane and P. Gafkan for mass spectrometry analyses; K. Smythe for technical assistance; and S. Riddell for comments on the manuscript. This work was supported by the Cancer Research Institute (B.K.K.), the Spanish Fondo de Investigaciones Sanitarias (S.G.), the Deutsche Forschungsgemeinschaft (H.H.M.), the Edson Fund, the Avon Foundation Breast Cancer Immunotherapy Research Initiative, and by grants from the NIH.

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Correspondence to Thomas Spies.

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Kaiser, B., Yim, D., Chow, IT. et al. Disulphide-isomerase-enabled shedding of tumour-associated NKG2D ligands. Nature 447, 482–486 (2007).

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