Wang Xuanjun, Lundgren Ashley D, Singh Pragya, Goodlett David R, Plymate Stephen R, Wu Jennifer D
Department of Medicine, University of Washington, 325 9th Ave., Seattle, WA 98104, USA.
Biochem Biophys Res Commun. 2009 Sep 25;387(3):476-81. doi: 10.1016/j.bbrc.2009.07.062. Epub 2009 Jul 16.
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.
肿瘤细胞表面的主要组织相容性复合体I类链相关分子A和B（MICA/B）的表达可向免疫受体NKG2D发出信号，以进行肿瘤免疫破坏。然而，在癌症患者中发现肿瘤会释放MIC，这会对宿主免疫产生负调节作用，并促进肿瘤免疫逃逸和进展。尽管有人提出多种酶参与其中，但肿瘤释放MIC的机制尚不清楚。这些酶的功能复杂性使其成为抑制MIC释放的不可行治疗靶点。在这里，我们在MIC的α3结构域中鉴定出一个六氨基酸（6-aa）基序，该基序对于MIC与ERp5相互作用以实现脱落至关重要。该基序中的突变可阻止MIC脱落，但不干扰NKG2D介导的对MIC的识别。我们的研究表明，6-aa基序是抑制MIC脱落用于癌症治疗的可行靶点。
