Cutting edge: the metalloproteinase ADAM17/TNF-alpha-converting enzyme regulates proteolytic shedding of the MHC class I-related chain B protein.
MHC class I-related chain (MIC) A/B are transmembrane proteins expressed in pathological conditions that are ligands for the activating receptor NKG2D found on cytotoxic lymphocytes. Soluble NKG2D ligands are detected in sera of patients suffering from multiple types of cancer where they are associated with reduced levels of receptor expression and compromised function of NK and CTLs. In this study, we report the identification of a metalloproteinase involved in the cleavage process of MIC; inhibition and knockdown of ADAM17/TACE blocks the shedding of these proteins. Strikingly, the recruitment of both enzyme and substrate to detergent-resistant membrane microdomains is crucial for efficient proteolysis. These findings provide a novel insight into the molecular mechanisms of MIC shedding.
Boutet
Philippe
P
Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
Agüera-González
Sonia
S
Atkinson
Susan
S
Pennington
Caroline J
CJ
Edwards
Dylan R
DR
Murphy
Gillian
G
Reyburn
Hugh T
HT
Valés-Gómez
Mar
M
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D000072198:ADAM17 Protein; D002460:Cell Line; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D021962:Membrane Microdomains / Q000201:enzymology / Q000378:metabolism*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D012995:Solubility; D013876:Thiophenes / Q000494:pharmacology
D004151:Dipeptides; D015395:Histocompatibility Antigens Class I; C098080:MICB antigen; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human