An six-amino acid motif in the alpha3 domain of MICA is the cancer therapeutic target to inhibit shedding.
Expression of the MHC class I chain related molecules A and B (MICA/B) on tumor cell surface can signal the immune receptor NKG2D for tumor immune destruction. However, MIC was found to be shed by tumors in cancer patients, which negatively regulates host immunity and promotes tumor immune evasion and progression. The mechanisms by which tumors shed MIC are not well understood although diverse groups of enzymes are suggested to be involved. The functional complexity of these enzymes makes them unfeasible therapeutic targets for inhibiting MIC shedding. Here we identified an six-amino acid (6-aa) motif in the alpha3 domain of MIC that is critical for the interaction of MIC with ERp5 to enable shedding. Mutations in this motif prevented MIC shedding but did not interfere with NKG2D-mediated recognition of MIC. Our study suggests that the 6-aa motif is a feasible target to inhibit MIC shedding for cancer therapy.
Wang
Xuanjun
X
Department of Medicine, University of Washington, 325 9th Ave., Seattle, WA 98104, USA.
Lundgren
Ashley D
AD
Singh
Pragya
P
Goodlett
David R
DR
Plymate
Stephen R
SR
Wu
Jennifer D
JD
D020816:Amino Acid Motifs / Q000187:drug effects / Q000235:genetics; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism*; D019704:Protein Disulfide-Isomerases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000235:genetics
D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; C496931:PDIA6 protein, human; D019704:Protein Disulfide-Isomerases