Ligand-dependent downregulation of MR1 cell surface expression.
Ligand-dependent downregulation of MR1 cell surface expression.
复制标题
MR1 细胞表面表达的配体依赖性下调。
DOI：
10.1073/pnas.2003136117
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发表时间：
2020
影响因子：
11.1
通讯作者：
Cerundolo,Vincenzo
中科院分区：
文献类型：
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作者：
Salio,Mariolina;Awad,Wael;Veerapen,Natacha;Gonzalez-Lopez,Claudia;Kulicke,Corinna;Waithe,Dominic;Martens,AnneWJ;Lewinsohn,DavidM;Hobrath,JudithV;Cox,LiamR;Rossjohn,Jamie;Besra,GurdyalS;Cerundolo,Vincenzo
抗原呈递分子MR1向粘膜相关不变T （MAIT）细胞呈递核黄素代谢物。虽然MR1向细胞表面的输出依赖于配体，但小分子配体影响MR1细胞运输的能力仍然未知。从MR1配体结合袋的硅屏幕上，我们鉴定了一个配体，3 -（[2,6-二氧基1,2,3,6-四氢嘧啶-4-基]甲氨基）丙酸，DB28，以及一个类似物，甲基3-（[2,6-二氧基1,2,3,6-四氢嘧啶-4-基]甲氨基）丙酸，NV18.1，从细胞表面下调MR1，并将MR1分子以未成熟的形式保留在内质网（ER）中。DB28和NV18.1与已知的MR1配体5-OP-RU和acetyl-6-FP竞争MR1结合并抑制MR1依赖性MAIT细胞活化。MAIT T细胞受体（TCR）与MR1- db28和MR1- nv18.1络合的晶体结构表明，这两个配体位于MR1的A ' -口袋内。两种配体都不能与MR1分子形成希夫碱；然而，两者都被疏水和极性接触的网络所隔离。因此，我们定义了一类抑制MR1细胞运输的化合物。
The antigen-presenting molecule MR1 presents riboflavin-based metabolites to Mucosal-Associated Invariant T (MAIT) cells. While MR1 egress to the cell surface is ligand-dependent, the ability of small-molecule ligands to impact on MR1 cellular trafficking remains unknown. Arising from an in silico screen of the MR1 ligand-binding pocket, we identify one ligand, 3-([2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]formamido)propanoic acid, DB28, as well as an analog, methyl 3-([2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]formamido)propanoate, NV18.1, that down-regulate MR1 from the cell surface and retain MR1 molecules in the endoplasmic reticulum (ER) in an immature form. DB28 and NV18.1 compete with the known MR1 ligands, 5-OP-RU and acetyl-6-FP, for MR1 binding and inhibit MR1-dependent MAIT cell activation. Crystal structures of the MAIT T cell receptor (TCR) complexed with MR1-DB28 and MR1-NV18.1, show that these two ligands reside within the A′-pocket of MR1. Neither ligand forms a Schiff base with MR1 molecules; both are nevertheless sequestered by a network of hydrophobic and polar contacts. Accordingly, we define a class of compounds that inhibits MR1 cellular trafficking.