BCA2/Rabring7 promotes tetherin-dependent HIV-1 restriction.
BCA2/Rabring7 promotes tetherin-dependent HIV-1 restriction.
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DOI：
10.1371/journal.ppat.1000700
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发表时间：
2009-12
期刊：
影响因子：
6.7
通讯作者：
Yamamoto N
中科院分区：
文献类型：
--
作者：
Miyakawa K;Ryo A;Murakami T;Ohba K;Yamaoka S;Fukuda M;Guatelli J;Yamamoto N
宿主细胞因子可以正向或负向调节 HIV-1 颗粒从受感染细胞中的组装和排出。最近的报告发现了一种以前未表征的跨膜蛋白，tetherin/CD317/BST-2，作为一种关键的宿主限制因子，通过抑制病毒颗粒的释放，在 HIV-1 复制的后期出芽步骤中发挥作用。尽管系链蛋白已被证明可以促进新生病毒颗粒保留在宿主细胞表面上，但在这些系链事件期间和之后发生的精确分子机制仍然很大程度上未知。我们在此报告，RING 型 E3 泛素连接酶 BCA2（乳腺癌相关基因 2；也称为 Rabring7、ZNF364 或 RNF115）是一种新型的 tetherin 相互作用宿主蛋白，有助于限制 tetherin 阳性细胞中 HIV-1 颗粒的产生。人类 BCA2 在“tetherin 阳性”HeLa 细胞中表达，但在“tetherin 阴性”HOS 细胞中不表达，导致 HIV-1 颗粒产生受到强烈限制。当 Tetherin 在 HOS 细胞中表达时，BCA2 能够像在 HeLa 细胞中一样抑制病毒颗粒的产生。在 HeLa 细胞中，通过 RNA 干扰 (RNAi) 有针对性地消耗内源性 BCA2，减少了病毒颗粒的细胞内积累，但病毒颗粒仍保留在质膜上。 BCA2 还被发现可以促进 HIV-1 病毒粒子内化到 CD63+ 细胞内囊泡中，从而导致其溶酶体降解。这些结果表明，BCA2 在病毒颗粒束缚于细胞表面后加速病毒颗粒的内化和降解，并且是依赖于束缚蛋白限制受感染细胞中 HIV-1 释放的辅助因子或增强剂。人体细胞拥有多个系统，使其能够抵抗病毒感染。最近，一种跨膜蛋白，tetherin，被鉴定为 HIV-1 感染细胞中的抗病毒宿主因子。 Tetherin 将新组装的病毒粒子保留在质膜上，并防止病毒从受感染的细胞中释放。然而，病毒粒子束缚后的精确分子机制仍然很大程度上未知。在我们目前的研究中，我们发现了一种 RING 型 E3 泛素连接酶 BCA2，它与人类细胞中的系链蛋白共定位并相互作用。研究发现 BCA2 可以促进质膜上 Tetherin 捕获的 HIV-1 颗粒的内化，并增强病毒颗粒对溶酶体的靶向性。相反，内源性 BCA2 的靶向消耗会减少病毒颗粒的细胞内积累。此外，一种小病毒蛋白 Vpu（tetherin 的拮抗剂）的表达会抵消 BCA2 的抗病毒作用。这些结果表明，BCA2 是一种潜在的抗病毒因子，可与系链蛋白协同作用，促进新生 HIV-1 颗粒在“系链后”过程中降解。
Host cell factors can either positively or negatively regulate the assembly and egress of HIV-1 particles from infected cells. Recent reports have identified a previously uncharacterized transmembrane protein, tetherin/CD317/BST-2, as a crucial host restriction factor that acts during a late budding step in HIV-1 replication by inhibiting viral particle release. Although tetherin has been shown to promote the retention of nascent viral particles on the host cell surface, the precise molecular mechanisms that occur during and after these tethering events remain largely unknown. We here report that a RING-type E3 ubiquitin ligase, BCA2 (Breast cancer-associated gene 2; also called Rabring7, ZNF364 or RNF115), is a novel tetherin-interacting host protein that facilitates the restriction of HIV-1 particle production in tetherin-positive cells. The expression of human BCA2 in “tetherin-positive” HeLa, but not in “tetherin-negative” HOS cells, resulted in a strong restriction of HIV-1 particle production. Upon the expression of tetherin in HOS cells, BCA2 was capable of inhibiting viral particle production as in HeLa cells. The targeted depletion of endogenous BCA2 by RNA interference (RNAi) in HeLa cells reduced the intracellular accumulation of viral particles, which were nevertheless retained on the plasma membrane. BCA2 was also found to facilitate the internalization of HIV-1 virions into CD63+ intracellular vesicles leading to their lysosomal degradation. These results indicate that BCA2 accelerates the internalization and degradation of viral particles following their tethering to the cell surface and is a co-factor or enhancer for the tetherin-dependent restriction of HIV-1 release from infected cells. Human cells possess multiple systems that render them resistant to viral infection. Recently, a transmembrane protein, tetherin, has been identified as an antiviral host factor in HIV-1-infected cells. Tetherin retains newly assembled virions at the plasma membrane and prevents viral release from the infected cells. However, the precise molecular mechanisms following the virion tethering remain largely unknown. In our current study, we have identified a RING-type E3 ubiquitin ligase, BCA2, which co-localizes and interacts with tetherin in human cells. BCA2 was found to facilitate the internalization of HIV-1 particles captured by tetherin on the plasma membrane and to enhance the targeting of viral particles to the lysosomes. Conversely, the targeted depletion of endogenous BCA2 reduces the intracellular accumulation of viral particles. Additionally, the expression of a small viral protein Vpu, an antagonist of tetherin, counteracts the antiviral effects of BCA2. These results suggest that BCA2 is a potential antiviral factor that collaborates with tetherin to facilitate the degradation of nascent HIV-1 particles during “post-tethering” processes.
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影响因子：
64.8
作者：
COHEN, EA;TERWILLIGER, EF;HASELTINE, WA
通讯作者：
HASELTINE, WA
影响因子：
5.4
作者：
Harila, K;Prior, I;Suomalainen, M
通讯作者：
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影响因子：
5.4
作者：
CHEN, MY;MALDARELLI, F;STREBEL, K
通讯作者：
STREBEL, K
DOI：
10.1016/j.bbrc.2007.04.052
发表时间：
2007-06-15
影响因子：
3.1
作者：
Sakane, Ayuko;Hatakeyama, Shigetsugu;Sasaki, Takuya
通讯作者：
Sasaki, Takuya
影响因子：
5.4
作者：
ADACHI, A;GENDELMAN, HE;MARTIN, MA
通讯作者：
MARTIN, MA