SAMHD1 Inhibits Multiple Enteroviruses by Interfering with the Interaction between VP1 and VP2 Proteins
SAMHD1 Inhibits Multiple Enteroviruses by Interfering with the Interaction between VP1 and VP2 Proteins
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SAMHD1 通过干扰 VP1 和 VP2 蛋白之间的相互作用来抑制多种肠道病毒
DOI：
10.1128/jvi.00620-21
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发表时间：
2021-04
影响因子：
5.4
通讯作者：
Zhang Wenyan
中科院分区：
文献类型：
--
作者：
Zhao Zhilei;Li Zhaolong;Huan Chen;Liu Xin;Zhang Wenyan
不育α基序和组氨酸天冬氨酸结构域含蛋白1(SAMHD1)具有病毒抑制、天然免疫调节和自身免疫等多种生物学活性。我们先前的研究表明，SAMHD1有效地抑制了肠道病毒71型(EV71)的复制。在本研究中，我们观察到SAMHD1还限制多种肠道病毒，包括柯萨奇病毒A16(CA16)和肠道病毒D68(EVD68)，但不限制柯萨奇病毒A6(CA6)。从机制上讲，SAMHD1竞争性地与VP1中与EV71和EVD68的VP2结合的相同结构域相互作用，从而干扰VP1和VP2之间的相互作用，从而干扰病毒组装。此外，我们还发现SAMHD1 T592a突变体通过减弱VP1和VP2之间的相互作用而保持了对EV71的抑制作用，而T592D突变体则未能做到这一点。我们还证明了SAMHD1不能抑制CA6，因为SAMHD1和VP1的相互作用需要不同的结合部位。我们的发现揭示了SAMHD1抑制多种EV的机制，这可能对开发针对广泛EV的药物具有重要意义。输入性肠道病毒导致多种疾病，如手足口病，这是一个威胁5 岁以下儿童的严重公共问题。因此，寻找限制EV感染的必需基因并探索其潜在机制，对于制定有效的抑制EV感染的策略是必要的。在这项研究中，我们报道了宿主限制因子SAMHD1对EV71、CA16和EVD68具有广谱的抗病毒活性，而不依赖于其众所周知的脱氧核苷三磷酸水解酶(DNTPase)或核糖核酸酶(RNase)活性。从机制上讲，SAMHD1通过与EVS的VP1中与VP2结合的相同结构域竞争性相互作用来限制EVS，从而干扰VP1和VP2之间的相互作用，从而干扰病毒组装。相反，我们也证明了SAMHD1不能抑制CA6，因为SAMHD1和CA6VP1相互作用需要不同的结合部位。我们的研究揭示了SAMHD1抗EV复制活性的新机制。
Sterile alpha motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1) possesses multiple biological activities such as virus restriction, innate immunity regulation, and autoimmunity. Our previous study demonstrated that SAMHD1 potently inhibits the replication of enterovirus 71 (EV71). In this study, we observed that SAMHD1 also restricts multiple enteroviruses (EVs), including coxsackievirus A16 (CA16) and enterovirus D68 (EVD68), but not coxsackievirus A6 (CA6). Mechanistically, SAMHD1 competitively interacted with the same domain in VP1 that binds to VP2 of EV71 and EVD68, thereby interfering with the interaction between VP1 and VP2 , and therefore viral assembly. Moreover, we showed that the SAMHD1 T592A mutant maintained the EV71 inhibitory effect by attenuating the interaction between VP1 and VP2, whereas the T592D mutant failed to. We also demonstrated that SAMHD1 could not inhibit CA6 because a different binding site is required for the SAMHD1 and VP1 interaction. Our findings reveal the mechanism of SAMHD1 inhibition of multiple EVs, and this could potentially be important for developing drugs against a broad range of EVs.IMPORTANCEEnterovirus causes a wide variety of diseases, such as hand, foot, and mouth disease (HFMD), which is a severe public problem threatening children under 5 years. Therefore, identifying essential genes which restrict EV infection and exploring the underlying mechanisms are necessary to develop an effective strategy to inhibit EV infection. In this study, we report that host restrictive factor SAMHD1 has broad-spectrum antiviral activity against EV71, CA16, and EVD68 independent of its well-known deoxynucleoside triphosphate triphosphohydrolase (dNTPase) or RNase activity. Mechanistically, SAMHD1 restricts EVs by competitively interacting with the same domain in VP1 that binds to VP2 of EVs, thereby interfering with the interaction between VP1 and VP2, and therefore viral assembly. In contrast, we also demonstrated that SAMHD1 could not inhibit CA6 because a different binding site is required for the SAMHD1 and CA6 VP1 interaction. Our study reveals a novel mechanism for the SAMHD1 anti-EV replication activity.
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影响因子：
6.7
作者：
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影响因子：
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作者：
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通讯作者：
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