Unconventional ligand activation of herpesvirus entry mediator signals cell survival
Unconventional ligand activation of herpesvirus entry mediator signals cell survival
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DOI：
10.1073/pnas.0902115106
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发表时间：
2009-04-14
影响因子：
11.1
通讯作者：
Ware, Carl F.
中科院分区：
文献类型：
--
作者：
Cheung, Timothy C.;Steinberg, Marcos W.;Ware, Carl F.
疱疹病毒进入介质（HVEM; TNFRSF14）通过典型的tnf相关细胞因子LIGHT激活NF-kappa B，在T细胞激活过程中作为共刺激途径。HVEM还作为Ig超家族成员B和T淋巴细胞衰减剂（BTLA）和CD160的配体，两者都限制T细胞引发的炎症反应。新出现的证据表明BTLA也促进T细胞存活，但其与LIGHT亲密BTLA的结构差异不太可能作为HVEM的激活剂起作用。我们在这里证明了BTLA、CD160和单纯疱疹病毒包膜糖蛋白D （gD）作为HVEM的激活配体，促进NF-kappa B的激活和细胞存活。膜表达的BTLA和CD160，以及可溶性二聚体受体替代物BTLA- fc和gD-Fc特异性激活HVEM依赖性NF-kappa B。BTLA和CD160结合诱导TNF受体相关因子2 （TRAF2）的募集，而不是TRAF3，在粘膜上皮肿瘤细胞系中特异性激活RelA而不是RelB形式的NF-kappa B。此外，Btla(-/-) T细胞在激活后存活较差，但被Btla - fc拯救，这表明HVEM-BTLA双向信号可能是淋巴细胞和上皮细胞的关键细胞存活系统。
The herpesvirus entry mediator (HVEM; TNFRSF14) activates NF-kappa B through the canonical TNF-related cytokine LIGHT, serving as a costimulatory pathway during activation of T cells. HVEM also functions as a ligand for the Ig superfamily members B and T lymphocyte attenuator (BTLA) and CD160, both of which limit inflammatory responses initiated by T cells. Emerging evidence indicates BTLA also promotes T cell survival, but its structural differences from LIGHT intimate BTLA is unlikely to function as an activator of HVEM. We demonstrate here that BTLA, CD160, and herpes simplex virus envelope glycoprotein D (gD) function as activating ligands for HVEM, promoting NF-kappa B activation and cell survival. Membrane-expressed BTLA and CD160, as well as soluble dimeric receptor surrogates BTLA-Fc and gD-Fc specifically activated HVEM-dependent NF-kappa B. BTLA and CD160 engagement induced recruitment of TNF receptor-associated factor 2 (TRAF2), but not TRAF3, to HVEM that specifically activated the RelA but not the RelB form of NF-kappa B in a mucosal epithelial tumor cell line. Moreover, Btla(-/-) T cells survived poorly following activation but were rescued with BTLA-Fc, indicating HVEM-BTLA bidirectional signaling may serve as a critical cell-survival system for lymphoid and epithelial cells.