ML-SA1 and SN-2 inhibit endocytosed viruses through regulating TRPML channel expression and activity.
ML-SA1 and SN-2 inhibit endocytosed viruses through regulating TRPML channel expression and activity.
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DOI：
10.1016/j.antiviral.2021.105193
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发表时间：
2021-10
影响因子：
7.6
通讯作者：
Zhiqiang Xia;Yingying Ren;Songryong Li;Jiyuan Xu;Yingliang Wu;Zhijian Cao
中科院分区：
文献类型：
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作者：
Zhiqiang Xia;Yingying Ren;Songryong Li;Jiyuan Xu;Yingliang Wu;Zhijian Cao
瞬时受体电位粘脂蛋白 2 和 3（TRPML2 和 TRPML3）作为内体-溶酶体系统中的关键通道，与许多不同的细胞过程相关，包括离子释放、膜运输和自噬。特别是，它们还可以促进病毒进入宿主细胞并增强病毒感染。我们之前发现了两种选择性 TRPML 激动剂 ML-SA1 和 SN-2，它们在体外对 2 型登革热病毒 (DENV2) 和寨卡病毒 (ZIKV) 表现出抗病毒活性，但它们的抗病毒机制仍不清楚。在这里，我们报道ML-SA1可以通过下调TRPML2和TRPML3的表达来抑制DENV2复制，而另一种TRPML激活剂SN-2通过仅降低TRPML3的表达来抑制DENV2感染。一致地，TRPML2 和 TRPML3 的通道活性也被发现与 ML-SA1 对 DENV2 和 ZIKV 的抗病毒活性相关，但 SN-2 仅依赖于 TRPML3 通道活性。进一步的机制实验表明，ML-SA1和SN-2依赖于TRPML2和TRPML3，降低了晚期内体标记物Rab7的表达，表明这两种化合物可能通过促进囊泡从晚期内体运输到溶酶体，然后加速病毒的溶酶体降解来抑制病毒感染。正如预期的那样，ML-SA1 和 SN-2 均不抑制 I 型单纯疱疹病毒 (HSV-1)，其进入不依赖于内溶酶体网络。我们的工作共同揭示了 ML-SA1 和 SN-2 靶向 TRPML 通道的抗病毒机制，可能导致发现抑制内吞病毒的新候选药物。
Transient receptor potential mucolipin 2 and 3 (TRPML2 and TRPML3), as key channels in the endosomal-lysosomal system, are associated with many different cellular processes, including ion release, membrane trafficking and autophagy. In particular, they can also facilitate viral entry into host cells and enhance viral infection. We previously identified that two selective TRPML agonists, ML-SA1 and SN-2, that showed antiviral activities against dengue virus type 2 (DENV2) and Zika virus (ZIKV)in vitro, but their antiviral mechanisms are still elusive. Here, we reported that ML-SA1 could inhibit DENV2 replication by downregulating the expression of both TRPML2 and TRPML3, while the other TRPML activator, SN-2, suppressed DENV2 infection by reducing only TRPML3 expression. Consistently, the channel activities of both TRPML2 and TRPML3 were also found to be associated with the antiviral activity of ML-SA1 on DENV2 and ZIKV, but SN-2 relied only on TRPML3 channel activity. Further mechanistic experiments revealed that ML-SA1 and SN-2 decreased the expression of the late endosomal marker Rab7, dependent on TRPML2 and TRPML3, indicating that these two compounds likely inhibit viral infection by promoting vesicular trafficking from late endosomes to lysosomes and then accelerating lysosomal degradation of the virus. As expected, neither ML-SA1 nor SN-2 inhibited herpes simplex virus type I (HSV-1), whose entry is independent of the endolysosomal network. Together, our work reveals the antiviral mechanisms of ML-SA1 and SN-2 in targeting TRPML channels, possibly leading to the discovery of new drug candidates to inhibit endocytosed viruses.