TANK-binding kinase 1 attenuates PTAP-dependent retroviral budding through targeting endosomal sorting complex required for transport-I.
TANK-binding kinase 1 attenuates PTAP-dependent retroviral budding through targeting endosomal sorting complex required for transport-I.
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TANK 结合激酶 1 通过靶向运输 I 所需的内体分选复合物来减弱 PTAP 依赖性逆转录病毒出芽
DOI：
10.4049/jimmunol.1000262
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发表时间：
2011-03-01
期刊：
影响因子：
--
通讯作者：
Tang H
中科院分区：
文献类型：
--
作者：
Da Q;Yang X;Xu Y;Gao G;Cheng G;Tang H
逆转录病毒需要从产生细胞中发芽来传播感染。为了促进其萌发，一些病毒通过Gag多蛋白的晚期结构域与MVB机械组件之间的相互作用，劫持了通常用于运输和降解泛素化细胞蛋白的多囊泡体(MVB)途径。在本研究中，我们证明了TANK-BINDING KEK1(TANK-BINDING KEK1)直接与MVB途径中转运-I(ESCRT-I)所需的内体分选复合体的一个亚单位VPS37C相互作用，而不影响MVB的超微结构或一般功能。有趣的是，TBK1的过表达减弱，而TBK1的短发夹状RNA干扰以I型干扰素(IFN-I)非依赖的方式促进了HIV-1伪病毒从Vero细胞释放。短发夹状RNA下调TZM-bl细胞中TBK1的表达也促进了HIV-1NL4-3或Jr-CSF病毒的存活，而不涉及干扰素-I的诱导。此外，用嵌合的小鼠白血病病毒/p6(其PPPY基序被HIV-1的PTAP基序取代)感染TBK1缺陷的小鼠胚胎成纤维细胞，结果表明，缺乏TBK1显著促进了PTAP依赖的逆转录病毒的萌发，但不能促进PPPY依赖的逆转录病毒的萌发。最后，Tbk1对VPS37C的磷酸化可能调节病毒的萌发效率，因为在Vero细胞中过表达的Tbk1的激酶失活突变体(TBK1-K38A)加速了HIV-1假病毒的萌发。因此，TBK1通过与ESCRT-I复合体的VPS37C连接，通过VPS37C的磷酸化来控制依赖PTAP的逆转录病毒的萌发速度，这将成为一种不依赖于干扰素-I信号的宿主细胞防御新机制。
Retroviruses need to bud from producer cells to spread infection. To facilitate its budding, some virus hijacks the multivesicular body (MVB) pathway that is normally used to cargo and degrade ubiquitylated cellular proteins, through interaction between the late domain of Gag polyproteins and the components of MVB machinery. In this study, we demonstrated that TANK-binding kinase 1 (TBK1) directly interacted with VPS37C, a subunit of endosomal sorting complex required for transport-I (ESCRT-I) in the MVB pathway, without affecting the ultrastructure or general function of MVB. Interestingly, overexpression of TBK1 attenuated, whereas short hairpin RNA interference of TBK1 enhanced HIV-1 pseudovirus release from Vero cells in type I IFN (IFN-I)-independent manner. Down-regulation of TBK1 by short hairpin RNA in TZM-bl cells also enhanced live HIV-1 NL4-3 or JR-CSF virus budding without involvement of IFN-I induction. Furthermore, infection of TBK1-deficient mouse embryonic fibroblast cells with a chimeric murine leukemia virus/p6, whose PPPY motif was replaced by PTAP motif of HIV-1, showed that lack of TBK1 significantly enhanced PTAP-dependent, but not PPPY-dependent retrovirus budding. Finally, phosphorylation of VPS37C by TBK1 might regulate the viral budding efficiency, because overexpression of the kinase-inactive mutant of TBK1 (TBK1-K38A) in Vero cells accelerated HIV-1 pseudovirus budding. Therefore, through tethering to VPS37C of the ESCRT-I complex, TBK1 controlled the speed of PTAP-dependent retroviral budding through phosphorylation of VPS37C, which would serve as a novel mechanism of host cell defense independent of IFN-I signaling.
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