Identification of host DEAD-box RNA helicases that regulate cellular tropism of oncolytic Myxoma virus in human cancer cells.
Identification of host DEAD-box RNA helicases that regulate cellular tropism of oncolytic Myxoma virus in human cancer cells.
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DOI：
10.1038/s41598-017-15941-1
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发表时间：
2017-11-16
影响因子：
4.6
通讯作者：
McFadden G
中科院分区：
文献类型：
--
作者：
Rahman MM;Bagdassarian E;Ali MAM;McFadden G
粘液瘤病毒（MYXV），一种兔痘病毒，正在开发作为用于治疗多种人类癌症的溶瘤病毒治疗剂。MYXV对人类癌细胞的嗜性主要由调节病毒复制或先天抗病毒反应途径的细胞内信号网络介导。因此，MYXV对于大多数在抗病毒信号传导中具有缺陷的人类癌细胞是完全或部分允许的，但少数是不允许的，因为病毒感染在完成之前就中止了。为了鉴定与人类癌细胞中MYXV嗜性相关的宿主因子，我们在两种允许的人类癌细胞（HeLa和A549）、一种半允许的（786-0）和一种非允许的细胞系（PANC-1）中进行了针对58种人类DEAD盒RNA解旋酶的小干扰RNA（siRNA）文库筛选。五种宿主RNA解旋酶（DDX 3X、DDX 5、DHX 9、DHX 37、DDX 52）对最佳复制具有抑制作用，因此被分类为抗病毒，而三种其他细胞RNA解旋酶（DHX 29、DHX 35、RIG-I）被鉴定为前病毒或前细胞，因为敲低一致地减少MYXV复制和/或允许癌细胞所需的代谢功能。这些发现表明，MYXV的复制，很可能所有痘病毒，显着调节积极和消极的多个主机死亡盒RNA解旋酶。
Myxoma virus (MYXV), a Leporipoxvirus, is being developed as an oncolytic virotherapeutic for the treatment of a variety of human cancers. MYXV tropism for human cancer cells is largely mediated by intracellular signaling networks that regulate viral replication or innate antiviral response pathways. Thus, MYXV is fully or partially permissive for the majority of human cancer cells that harbor defects in antiviral signaling, but a minority are nonpermissive because the virus infection aborts before its completion. To identify host factors relevant for MYXV tropism in human cancer cells, we performed a small interfering RNA (siRNA) library screen targeting the 58 human DEAD-box RNA helicases in two permissive human cancer cells (HeLa and A549), one semi-permissive (786-0), and one nonpermissive cell line (PANC-1). Five host RNA helicases (DDX3X, DDX5, DHX9, DHX37, DDX52) were inhibitory for optimal replication and thus classified as anti-viral, while three other cellular RNA helicases (DHX29, DHX35, RIG-I) were identified as pro-viral or pro-cellular because knockdown consistently reduced MYXV replication and/or required metabolic functions of permissive cancer cells. These findings suggest that replication of MYXV, and likely all poxviruses, is dramatically regulated positively and negatively by multiple host DEAD-box RNA helicases.
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