Alternative Splice Transcripts for MHC Class I–like MICA Encode Novel NKG2D Ligands with Agonist or Antagonist Functions
Alternative Splice Transcripts for MHC Class I–like MICA Encode Novel NKG2D Ligands with Agonist or Antagonist Functions
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MHC I 类 MICA 的替代剪接转录本编码具有激动剂或拮抗剂功能的新型 NKG2D 配体
作者：
Pierre;P. Tonnerre;N. Gérard;S. Nedellec;Andrew W. Daman;B. McFarland;B. Charreau
MHC I类链相关蛋白A和B（云母和MIC B）以及UL 16结合蛋白是参与癌症和感染免疫监视的活化NKG 2D受体的配体。在结构上，云母/B蛋白含有α3结构域，而UL 16结合蛋白不含。我们鉴定了云母的新型可变剪接转录本，其编码五种新型云母亚型：MICA-A、-B1、-B2、-C和-D。选择性剪接与云母 *015和 *017相关，是云母内含子4的5′剪接供体位点的点缺失（G）导致外显子3和外显子4跳读和/或缺失的结果。这些变化删除了所有亚型中的α3结构域和大多数亚型（A、B1、C和D）中的α2结构域。内皮细胞和造血细胞含有内源性选择性剪接转录本和亚型。MICA-B1、-B2和-D通过表面等离子体共振结合NKG 2D，并在细胞表面表达。在功能上，MICA-B2含有两个胞外结构域（α1和α2），是NKG 2D的新型强效激动剂配体。我们发现MICA-D是云母的一种新的截短形式，尽管缺乏α2和α3结构域，但对NKG 2D的亲和力较弱。MICA-D可能通过与全长云母或MICA-B2竞争NKG 2D结合而在功能上损害NKG 2D活化。我们的研究确定了NKG 2D与重组MICA-B1的结合，但未发现该亚型的功能。新的截短云母亚型表现出一系列功能，可能会驱动意想不到的免疫机制，并为免疫治疗提供新工具。
MHC class I chain–related proteins A and B (MICA and MICB) and UL16-binding proteins are ligands of the activating NKG2D receptor involved in cancer and immune surveillance of infection. Structurally, MICA/B proteins contain an α3 domain, whereas UL16-binding proteins do not. We identified novel alternative splice transcripts for MICA encoding five novel MICA isoforms: MICA-A, -B1, -B2, -C, and -D. Alternative splicing associates with MICA*015 and *017 and results from a point deletion (G) in the 5′ splice donor site of MICA intron 4 leading to exon 3 and exon 4 skipping and/or deletions. These changes delete the α3 domain in all isoforms, and the α2 domain in the majority of isoforms (A, B1, C, and D). Endothelial and hematopoietic cells contained endogenous alternative splice transcripts and isoforms. MICA-B1, -B2, and -D bound NKG2D by surface plasmon resonance and were expressed at the cell surface. Functionally, MICA-B2 contains two extracellular domains (α1 and α2) and is a novel potent agonist ligand for NKG2D. We found that MICA-D is a new truncated form of MICA with weak affinity for NKG2D despite lacking α2 and α3 domains. MICA-D may functionally impair NKG2D activation by competing with full-length MICA or MICA-B2 for NKG2D engagement. Our study established NKG2D binding for recombinant MICA-B1 but found no function for this isoform. New truncated MICA isoforms exhibit a range of functions that may drive unexpected immune mechanisms and provide new tools for immunotherapy.
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影响因子：
56.9
作者：
Bauer, S;Groh, V;Spies, T
通讯作者：
Spies, T
DOI：
10.1073/pnas.93.22.12445
发表时间：
1996-10-29
影响因子：
11.1
作者：
Groh, V;Bahram, S;Spies, T
通讯作者：
Spies, T
DOI：
10.1073/pnas.89.9.3947
发表时间：
1992-05-01
影响因子：
11.1
作者：
ISHITANI, A;GERAGHTY, DE
通讯作者：
GERAGHTY, DE
影响因子：
32.4
作者：
Ogasawara, K;Hamerman, JA;Lanier, LL
通讯作者：
Lanier, LL
DOI：
10.1016/j.bbrc.2009.07.062
发表时间：
2009-09-25
影响因子：
3.1
作者：
Wang, Xuanjun;Lundgren, Ashley D.;Singh, Pragya;Goodlett, David R.;Plymate, Stephen R.;Wu, Jennifer D.
通讯作者：
Wu, Jennifer D.