Ligand-induced interactions between butyrophilin 2A1 and 3A1 internal domains in the HMBPP receptor complex.
Ligand-induced interactions between butyrophilin 2A1 and 3A1 internal domains in the HMBPP receptor complex.
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DOI：
10.1016/j.chembiol.2022.01.004
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发表时间：
2022-06-16
影响因子：
8.6
通讯作者：
Wiemer, Andrew J.
中科院分区：
文献类型：
--
作者：
Hsiao, Chia-Hung Christine;Nguyen, Khiem;Jin, Yiming;Vinogradova, Olga;Wiemer, Andrew J.
Vγ9Vδ2T细胞的TCR可检测到配体结合的HMBPP受体(BTN3A1和BTN2A1)。虽然BTN3A1与磷酸抗原结合，但导致受体激活的机制尚不清楚。我们使用CRISPR/Cas9、ELISA、Nano-Bret和ITC来评估BTN2A1的作用。BTN2A1的耗尽和挽救实验表明，其内部结构域对于PAg检测是必不可少的。在BTN2A1和BTN3A1之间观察到了内部异质Bret信号，这两个信号被PAg增加。ITC仅在PAg存在的情况下才检测到BTN3A1和BTN2A1的胞内结构域之间的直接相互作用。这种相互作用可通过移除BTN2A1 JM区来消除，但不能通过移除BTN3A1 JM区来消除。BTN2A1316-326区域突变明显影响干扰素γ应答和异源突变信号。氨基酸L318、W320和L325的突变表明这些氨基酸是至关重要的。综上所述，这些研究表明BTN2A1和BTN3A1内部结构域之间存在PAG诱导的相互作用。Hsiao et al.鉴定和鉴定BTN2A1和BTN3A1内部结构域之间依赖于磷酸抗原的相互作用，这是Vγ9Vδ2T细胞对磷抗原反应所必需的。这种相互作用已经定位在BTN2A1蛋白的一个区域，并确定了功能所需的氨基酸。
Ligand-bound HMBPP receptor (BTN3A1 and BTN2A1) is detectable by the TCR of Vγ9Vδ2 T cells. While BTN3A1 binds to phosphoantigens, the mechanisms resulting in receptor activation are not clear. We used CRISPR/Cas9, ELISA, nano-BRET and ITC to evaluate the role of BTN2A1. Depletion of BTN2A1 and rescue experiments demonstrate that its internal domain is essential for pAg detection. Internal hetero-BRET signals are observed between BTN2A1 and BTN3A1, which are increased by pAg. ITC detects a direct interaction between the intracellular domains of BTN3A1 and BTN2A1, only in the presence of pAg. This interaction is abrogated by removal of the BTN2A1 JM region, but not by removal of the BTN3A1 JM region. Regional mutations between BTN2A1 316–326 clearly impact IFNγ response and hetero-BRET signal. Mutations to amino acids L318, W320, and L325 indicate these amino acids are crucial. Together, these studies demonstrate a pAg-inducible interaction between BTN2A1 and BTN3A1 internal domains. Hsiao et al. identify and characterize a phosphoantigen dependent interaction between BTN2A1 and BTN3A1 internal domains which is necessary for the Vγ9Vδ2 T cell response to phosphoantigen. The interaction has been localized to a region in the BTN2A1 protein and amino acids that are required for function have been identified.
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