Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Max-von-Laue Str. 9, 60438 Frankfurt, Germany.
Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239.
J Biol Chem. 2011 Dec 2;286(48):41402-41412. doi: 10.1074/jbc.M111.237784. Epub 2011 Oct 7.
Virus-infected cells are eliminated by cytotoxic T lymphocytes, which recognize viral epitopes displayed on major histocompatibility complex class I molecules at the cell surface. Herpesviruses have evolved sophisticated strategies to escape this immune surveillance. During the lytic phase of EBV infection, the viral factor BNLF2a interferes with antigen processing by preventing peptide loading of major histocompatibility complex class I molecules. Here we reveal details of the inhibition mechanism of this EBV protein. We demonstrate that BNLF2a acts as a tail-anchored protein, exploiting the mammalian Asna-1/WRB (Get3/Get1) machinery for posttranslational insertion into the endoplasmic reticulum membrane, where it subsequently blocks antigen translocation by the transporter associated with antigen processing (TAP). BNLF2a binds directly to the core TAP complex arresting the ATP-binding cassette transporter in a transport-incompetent conformation. The inhibition mechanism of EBV BNLF2a is distinct and mutually exclusive of other viral TAP inhibitors.
被病毒感染的细胞会被细胞毒性 T 淋巴细胞清除，后者能够识别细胞表面主要组织相容性复合体 I 类分子上呈现的病毒表位。疱疹病毒已经进化出了复杂的策略来逃避这种免疫监视。在 EBV 感染的裂解期，病毒因子 BNLF2a 通过阻止主要组织相容性复合体 I 分子的肽加载来干扰抗原加工。在这里，我们揭示了这种 EBV 蛋白抑制机制的细节。我们证明 BNLF2a 作为一种尾部锚定蛋白，利用哺乳动物 Asna-1/WRB（Get3/Get1）机制进行翻译后插入内质网膜，随后通过抗原加工相关转运体（TAP）阻止抗原易位。BNLF2a 直接结合到 TAP 核心复合物上，使 ABC 转运体在运输无能力构象中停滞。EBV BNLF2a 的抑制机制与其他病毒 TAP 抑制剂不同，是相互排斥的。
