The Gammaherpesvirus m2 protein manipulates the Fyn/Vav pathway through a multidocking mechanism of assembly.
The Gammaherpesvirus m2 protein manipulates the Fyn/Vav pathway through a multidocking mechanism of assembly.
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DOI：
10.1371/journal.pone.0001654
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发表时间：
2008-02-27
期刊：
影响因子：
3.7
通讯作者：
Simas JP
中科院分区：
文献类型：
--
作者：
Pires de Miranda M;Alenquer M;Marques S;Rodrigues L;Lopes F;Bustelo XR;Simas JP
为了在B细胞中建立潜伏感染，伽马疱疹病毒在宿主被感染的B细胞中表达蛋白质，这些蛋白质虚假地激活位于B细胞受体下游的信号通路。M2就是这样的一种蛋白质，它是一种小鼠伽马疱疹病毒68编码的分子，通过与SCR家族成员形成三分子复合体来激活Vav1/rac1途径。以前的报道表明，这种异分子复合体的形成涉及M2的一个富含脯氨酸的区域与Vav1和Fyn SH3结构域之间的相互作用。在这里，我们证明了这些蛋白质的最佳结合需要包含两个酪氨酸残基(Tyr120和129)的第二个结构基序。这些残基在非造血细胞中被Fyn诱导磷酸化，在B细胞中被结构性磷酸化。我们还证明了Tyr120的磷酸化为Vav1和Fyn的SH2结构域创建了特定的对接位置，这是这两个信号蛋白在体内最佳结合的必要条件。有趣的是，信号实验表明，M2在B细胞中的表达促进了Vav1和其他信号蛋白的酪氨酸磷酸化，这一生物过程需要M2磷酸酪氨酸和富含脯氨酸的区域基序的完整性。通过用M2基因突变的病毒感染小鼠，我们证明了这两个M2对接基序的完整性对于小鼠伽马疱疹病毒-68潜伏的早期步骤是必不可少的。综上所述，这些结果表明M2磷酸酪氨酸基序和前面描述的M2富含脯氨酸区域协同工作，操纵宿主B细胞的信号机制。
To establish latent infections in B-cells, gammaherpesviruses express proteins in the infected B-cells of the host that spuriously activate signalling pathways located downstream of the B-cell receptor. One such protein is M2, a murine gammaherpesvirus 68-encoded molecule that activates the Vav1/Rac1 pathway via the formation of trimolecular complexes with Scr family members. Previous reports have shown that the formation of this heteromolecular complex involves interactions between a proline rich region of M2 and the Vav1 and Fyn SH3 domains. Here, we show that the optimal association of these proteins requires a second structural motif encompassing two tyrosine residues (Tyr120 and 129). These residues are inducibly phosphorylated by Fyn in non-hematopoietic cells and constitutively phosphorylated in B-cells. We also demonstrate that the phosphorylation of Tyr120 creates specific docking sites for the SH2 domains of both Vav1 and Fyn, a condition sine qua non for the optimal association of these two signalling proteins in vivo. Interestingly, signaling experiments indicate that the expression of M2 in B-cells promotes the tyrosine phosphorylation of Vav1 and additional signaling proteins, a biological process that requires the integrity of both the M2 phosphotyrosine and proline rich region motifs. By infecting mice with viruses mutated in the m2 locus, we show that the integrity of each of these two M2 docking motifs is essential for the early steps of murine gammaherpesvirus-68 latency. Taken together, these results indicate that the M2 phosphotyrosine motif and the previously described M2 proline rich region work in a concerted manner to manipulate the signaling machinery of the host B-cell.
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影响因子：
5.3
作者：
López-Lago, M;Lee, K;Bustelo, XR
通讯作者：
Bustelo, XR
影响因子：
5.4
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Adler, H;Messerle, M;Koszinowski, UH
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Koszinowski, UH
影响因子：
15.3
作者：
Flaño, E;Kim, IJ;Blackman, MA
通讯作者：
Blackman, MA
影响因子：
5.4
作者：
Liang, Xiaozhen;Pickering, Mary T.;Jung, Jae U.
通讯作者：
Jung, Jae U.
影响因子：
5.4
作者：
Adler, H;Messerle, M;Koszinowski, UH
通讯作者：
Koszinowski, UH