HIV-1 Accessory Protein Vpu Internalizes Cell-surface BST-2/Tetherin through Transmembrane Interactions Leading to Lysosomes
HIV-1 Accessory Protein Vpu Internalizes Cell-surface BST-2/Tetherin through Transmembrane Interactions Leading to Lysosomes
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DOI：
10.1074/jbc.m109.058305
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发表时间：
2009-12-11
影响因子：
4.8
通讯作者：
Tokunaga, Kenzo
中科院分区：
文献类型：
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作者：
Iwabu, Yukie;Fujita, Hideaki;Tokunaga, Kenzo
骨髓基质抗原2 （BST-2，也称为tetherin）是最近发现的一种干扰素诱导的宿主限制因子，它可以通过在细胞表面捕获病毒颗粒来阻止包膜病毒的产生。这种抗病毒作用被人类免疫缺陷病毒1型（HIV-1）辅助蛋白病毒蛋白U （Vpu）抵消。在这里，我们发现HIV-1 Vpu通过它们相互的跨膜结构域与BST-2物理相互作用，并通过溶酶体而不是蛋白酶体途径导致该宿主因子的降解。这种降解部分由一种细胞蛋白控制，即含有β -转导蛋白重复序列的蛋白（β - TrCP），这是vpu诱导的CD4降解所必需的。重要的是，Vpu对BST-2的靶向作用发生在质膜上，随后Vpu对宿主蛋白的主动内化独立于组成性内吞作用。因此，Vpu的主要作用位点是质膜，Vpu通过跨膜相互作用靶向并内化细胞表面BST-2，导致溶酶体降解，部分以β - trcp依赖的方式降解。此外，我们提出了BST-2在将病毒粒子拴在细胞表面时的以下配置；每个二聚体BST-2分子都是病毒和细胞膜之间的桥梁。
Bone marrow stromal antigen 2 (BST-2, also known as tetherin) is a recently identified interferon-inducible host restriction factor that can block the production of enveloped viruses by trapping virus particles at the cell surface. This antiviral effect is counteracted by the human immunodeficiency virus type 1 (HIV-1) accessory protein viral protein U (Vpu). Here we show that HIV-1 Vpu physically interacts with BST-2 through their mutual transmembrane domains and leads to the degradation of this host factor via a lysosomal, not proteasomal, pathway. The degradation is partially controlled by a cellular protein, beta-transducin repeat-containing protein (beta TrCP), which is known to be required for the Vpu-induced degradation of CD4. Importantly, targeting of BST-2 by Vpu occurs at the plasma membrane followed by the active internalization of this host protein by Vpu independently of constitutive endocytosis. Thus, the primary site of action of Vpu is the plasma membrane, where Vpu targets and internalizes cell-surface BST-2 through transmembrane interactions, leading to lysosomal degradation, partially in a beta TrCP-dependent manner. Also, we propose the following configuration of BST-2 in tethering virions to the cell surface; each of the dimerized BST-2 molecules acts as a bridge between viral and cell membranes.