Identification of a novel immunosubversion mechanism mediated by a virologue of the B-lymphocyte receptor TACI
Identification of a novel immunosubversion mechanism mediated by a virologue of the B-lymphocyte receptor TACI
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DOI：
10.1128/cvi.00058-07
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发表时间：
2007-07-01
影响因子：
--
通讯作者：
Jefferies, Wilfred A.
中科院分区：
文献类型：
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作者：
Grant, Jason R.;Moise, Alexander R.;Jefferies, Wilfred A.
TACI（跨膜激活剂和钙调节剂和亲环素配体[CAML]相互作用物）是参与B细胞存活和同种型转换的新型配体和受体网络的一部分。TACI蛋白通过CAML介导其作用，CAML是一种控制Ca 2+流出的内质网（ER）定位蛋白。腺病毒E3-6.7K蛋白可预防炎症反应，并可抵抗各种凋亡刺激，维持ER Ca 2+稳态;然而，其作用机制尚不清楚。在这里，我们提供的证据表明，E3-6.7K股序列同源性TACI和抑制细胞凋亡和ER Ca 2+流出通过与CAML，钙调节蛋白的相互作用。我们证明了E3-6.7K和CAML之间的直接相互作用，并揭示了这两种蛋白质共定位在ER样隔室中。此外，两种蛋白之间的相互作用定位于CAML的N-末端结构域和E3-6.7K的C末端附近的22个氨基酸的区域，称为CAML结合结构域（CBD）。CBD的突变分析表明，E3-6.7K需要与CAML相互作用来抑制毒胡萝卜素诱导的细胞凋亡和ER Ca 2+流出。E3-6.7K似乎是第一个被鉴定的TACI病毒。它以一种新的免疫破坏机制靶向CAML，以改变ER Ca 2+稳态，从而抑制炎症并保护感染细胞免于凋亡。
TACI (transmembrane activator and calcium modulator and cyclophilin ligand [CAML] interactor) is a part of a novel network of ligands and receptors involved in B-cell survival and isotype switching. The TACI protein mediates its effects through CAML, an endoplasmic reticulum (ER)-localized protein that controls Ca2+ efflux. The adenovirus E3-6.7K protein prevents inflammatory responses and also confers resistance from a variety of apoptotic stimuli and maintains ER Ca2+ homeostasis; however, the mechanism of action is unknown. Here, we provide evidence that E3-6.7K shares sequence homology with TACI and inhibits apoptosis and ER Ca2+ efflux through an interaction with CAML, a Ca2+-modulating protein. We demonstrate a direct interaction between E3-6.7K and CAML and reveal that the two proteins colocalize in an ER-like compartment. Furthermore, the interaction between the two proteins is localized to the N-terminal domain of CAML and to a 22-amino-acid region near the C terminus of E3-6.7K termed the CAML-binding domain (CBD). Mutational analysis of the CBD showed that an interaction with CAML is required for E3-6.7K to inhibit thapsigargin-induced apoptosis and ER Ca2+ efflux. E3-6.7K appears to be the first virologue of TACI to be identified. It targets CAML in a novel immunosubversive mechanism to alter ER Ca2+ homeostasis, which consequently inhibits inflammation and protects infected cells from apoptosis.