The Human Cytomegalovirus Protein TRS1 Inhibits Autophagy via Its Interaction with Beclin 1
The Human Cytomegalovirus Protein TRS1 Inhibits Autophagy via Its Interaction with Beclin 1
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DOI：
10.1128/jvi.05746-11
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发表时间：
2012-03-01
影响因子：
5.4
通讯作者：
Esclatine, Audrey
中科院分区：
文献类型：
--
作者：
Chaumorcel, Magali;Lussignol, Marion;Esclatine, Audrey
人巨细胞病毒以两个相反的方向调节巨自噬。首先，HCMV 在感染的早期阶段刺激自噬，从自噬体数量的增加和自噬流的增加可以看出这一点。这种刺激的发生与病毒蛋白从头合成无关，因为紫外线灭活的 HCMV 重现了对巨自噬的刺激作用。在感染的后期时间点，HCMV 通过需要从头病毒蛋白表达的机制来阻断自噬（M. Chaumorcel、S. Souquere、G. Pierron、P. Codogno 和 A. Esclatine, Autophagy 4:1-8, 2008）。对 HCMV 阻断自噬机制的探索揭示了 Bcl-2 表达的细胞形式的强劲增加。尽管该蛋白通过与 Beclin 1 相互作用而具有抗自噬作用，但它并不负责 HCMV 诱导的抑制，可能是因为它被 c-Jun N 末端激酶磷酸化。在这里，我们表明 HCMV TRS1 蛋白阻断自噬体生物发生，并且 TRS1 缺失突变体在自噬抑制方面存在缺陷。 TRS1 先前已被证明可以中和 PKR 抗病毒效应分子。尽管 PKR 对 eIF2 α 的磷酸化被描述为诱导自噬的刺激信号，但 TRS1 的 PKR 结合结构域对其抑制作用来说是可有可无的。我们的结果表明，TRS1 与 Beclin 1 相互作用以抑制自噬。我们将与 Beclin 1 的相互作用映射到 TRS1 的 N 末端区域，并证明 TRS1 的 Beclin 1 结合域对于抑制自噬至关重要。
Human cytomegalovirus modulates macroautophagy in two opposite directions. First, HCMV stimulates autophagy during the early stages of infection, as evident by an increase in the number of autophagosomes and a rise in the autophagic flux. This stimulation occurs independently of de novo viral protein synthesis since UV-inactivated HCMV recapitulates the stimulatory effect on macroautophagy. At later time points of infection, HCMV blocks autophagy (M. Chaumorcel, S. Souquere, G. Pierron, P. Codogno, and A. Esclatine, Autophagy 4:1-8, 2008) by a mechanism that requires de novo viral protein expression. Exploration of the mechanisms used by HCMV to block autophagy unveiled a robust increase of the cellular form of Bcl-2 expression. Although this protein has an anti-autophagy effect via its interaction with Beclin 1, it is not responsible for the inhibition induced by HCMV, probably because of its phosphorylation by c-Jun N-terminal kinase. Here we showed that the HCMV TRS1 protein blocks autophagosome biogenesis and that a TRS1 deletion mutant is defective in autophagy inhibition. TRS1 has previously been shown to neutralize the PKR antiviral effector molecule. Although phosphorylation of eIF2 alpha by PKR has been described as a stimulatory signal to induce autophagy, the PKR-binding domain of TRS1 is dispensable to its inhibitory effect. Our results show that TRS1 interacts with Beclin 1 to inhibit autophagy. We mapped the interaction with Beclin 1 to the N-terminal region of TRS1, and we demonstrated that the Beclin 1-binding domain of TRS1 is essential to inhibit autophagy.