Structural and biochemical bases for the inhibition of autophagy and apoptosis by viral BCL-2 of murine gamma-herpesvirus 68.
Structural and biochemical bases for the inhibition of autophagy and apoptosis by viral BCL-2 of murine gamma-herpesvirus 68.
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鼠γ-疱疹病毒 68 的病毒 BCL-2 抑制自噬和细胞凋亡的结构和生化基础。
DOI：
10.1371/journal.ppat.0040025
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发表时间：
2008-02-08
期刊：
影响因子：
6.7
通讯作者：
Oh, Byung-Ha
中科院分区：
文献类型：
--
作者：
Ku, Bonsu;Woo, Jae-Sung;Liang, Chengyu;Lee, Kwang-Hoon;Hong, Hyang-Suk;Xiaofei, E.;Kim, Key-Sun;Jung, Jae U.;Oh, Byung-Ha
所有的伽马疱疹病毒都表达抗凋亡B细胞淋巴瘤-2(BCL-2)的同源物，以对抗宿主抗病毒防御机制对感染细胞的清除。为了深入了解这些病毒bcl2蛋白的作用机制，我们对小鼠γ疱疹病毒68的病毒bcl2基因M11与来自一系列促凋亡bcl2家族蛋白的前自噬Beclin1和bcl2同源3(BH3)结构域多肽的相互作用进行了结构和生化分析。M11主要通过疏水相互作用与Beclin1的BH3样结构域结合，其解离常数为40纳米摩尔，与细胞bcl2与Beclin1的1.7微摩尔结合亲和力相比明显更紧密。在NIH3T3细胞中，M11始终比bcl2更有效地抑制自噬。M11还与BAK的BH3结构域肽以及BIm、Bid、Bmf、PUMA和Noxa上游蛋白的BIm、Bid、BmF、PUMA和Noxa紧密相互作用，但与Bax的作用较弱。这些结果共同表明，M11除了广泛中和促凋亡的bcl2家族外，还能有效地抑制Beclin1，其方式与细胞bcl2相似但不同，Beclin1介导的自噬可能是病毒的主要靶点。在高等动物中，缺陷或多余的细胞通过一种称为细胞凋亡的过程被移除。另一方面，有缺陷或受损的细胞成分通过一种称为自噬的过程被移除。这两个破坏性的过程对于生物体的生存和发展是不可或缺的。虽然细胞凋亡被认为是清除病毒感染细胞的一种中央宿主防御机制，但自噬对病毒感染的作用最近才出现。许多病毒表达一大堆病毒蛋白，这些蛋白可以对抗细胞死亡介导的先天免疫控制。其中一种蛋白质是细胞内bcl2蛋白的同系物，它通过抑制与促凋亡蛋白的结合来抑制细胞凋亡。小鼠γ-疱疹病毒68还编码一种病毒bcl2，称为M11。在这项研究中，我们定量地测量了M11与其潜在的细胞靶点的结合亲和力，包括10种不同的促凋亡蛋白和自噬蛋白Beclin1。我们发现，M11广泛地中和促凋亡蛋白，而不是选择性地抑制细胞凋亡。令人惊讶的是，M11与Beclin1结合的亲和力最高，这与其在细胞内强大的抗自噬活性有关。这些数据表明，M11不仅能抑制细胞凋亡，还能有效地抑制自噬，最终导致病毒的慢性感染。
All gammaherpesviruses express homologues of antiapoptotic B-cell lymphoma-2 (BCL-2) to counter the clearance of infected cells by host antiviral defense machineries. To gain insights into the action mechanisms of these viral BCL-2 proteins, we carried out structural and biochemical analyses on the interactions of M11, a viral BCL-2 of murine γ-herpesvirus 68, with a fragment of proautophagic Beclin1 and BCL-2 homology 3 (BH3) domain-containing peptides derived from an array of proapoptotic BCL-2 family proteins. Mainly through hydrophobic interactions, M11 bound the BH3-like domain of Beclin1 with a dissociation constant of 40 nanomole, a markedly tighter affinity compared to the 1.7 micromolar binding affinity between cellular BCL-2 and Beclin1. Consistently, M11 inhibited autophagy more efficiently than BCL-2 in NIH3T3 cells. M11 also interacted tightly with a BH3 domain peptide of BAK and those of the upstream BH3-only proteins BIM, BID, BMF, PUMA, and Noxa, but weakly with that of BAX. These results collectively suggest that M11 potently inhibits Beclin1 in addition to broadly neutralizing the proapoptotic BCL-2 family in a similar but distinctive way from cellular BCL-2, and that the Beclin1-mediated autophagy may be a main target of the virus. In higher animals, defective or surplus cells are removed by a process known as apoptosis. On the other hand, defective or damaged cellular components are removed by a process known as autophagy. These two destructive processes are indispensable for the survival and development of an organism. While apoptosis is known as a central host defense mechanism that removes virus-infected cells, the role of autophagy against viral infection has recently emerged. Many viruses express an armory of viral proteins that counteract cell death–mediated innate immune control. One such protein is a homologue of the cellular BCL-2 protein that suppresses apoptosis through inhibitory binding to apoptosis-promoting proteins. Murine γ-herpesvirus 68 also encodes a viral BCL-2, known as M11. In this study, we quantitatively measured the binding affinity of M11 for its potential cellular targets, including ten different proapoptotic proteins and the proautophagic protein Beclin1. We found that M11 neutralizes the proapoptotic proteins broadly rather than selectively to suppress apoptosis. Surprisingly, M11 bound to Beclin1 with the highest affinity, which correlated with its strong antiautophagic activity in cells. These data suggest that M11 suppresses not only apoptosis but also autophagy potently, which ultimately contributes to the viral chronic infection.
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影响因子：
9.8
作者：
Altmann, Markus;Hammerschmidt, Wolfgang
通讯作者：
Hammerschmidt, Wolfgang
DOI：
10.1073/pnas.0701297104
发表时间：
2007-04-10
影响因子：
11.1
作者：
Czabotar, Peter E.;Lee, Erinna F.;Colman, Peter M.
通讯作者：
Colman, Peter M.
影响因子：
5.4
作者：
Derfuss, T;Fickenscher, H;Meinl, E
通讯作者：
Meinl, E
影响因子：
16
作者：
Kvansakul, Marc;van Delft, Mark F.;Colman, Peter M.
通讯作者：
Colman, Peter M.
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL