TRIM25 Binds RNA to Modulate Cellular Anti-viral Defense.
TRIM25 Binds RNA to Modulate Cellular Anti-viral Defense.
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DOI：
10.1016/j.jmb.2018.10.003
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发表时间：
2018-12-07
影响因子：
5.6
通讯作者：
Pornillos O
中科院分区：
文献类型：
--
作者：
Sanchez JG;Sparrer KMJ;Chiang C;Reis RA;Chiang JJ;Zurenski MA;Wan Y;Gack MU;Pornillos O
TRIM 25是一种多结构域的RING型E3泛素连接酶，在多种RNA依赖性过程中发挥重要作用。特别是，TRIM 25作为RIG-I和ZAP的效应子发挥作用，RIG-I和ZAP是识别病毒RNA并诱导泛素依赖性抗病毒应答机制的先天免疫传感器。据报道TRIM 25也结合RNA，但这种相互作用的分子细节或其与抗病毒防御的相关性尚未阐明。在这里，我们描述了TRIM 25的RNA结合活性，并发现该蛋白质结合单链和双链RNA。TRIM 25的多个区域有助于这种功能，包括C-末端SPRY结构域和连接SPRY和卷曲螺旋结构域的接头片段中的富含赖氨酸的基序。RNA结合调节TRIM 25的体外泛素化活性、其在细胞中的定位及其抗病毒活性。结合其他研究，我们的结果表明TRIM 25与RNA的结合至少具有三个重要的功能后果：通过变构效应或通过多个TRIM 25分子的聚集来增强遍在蛋白化活性;通过调节TRIM 25二聚体的多结构域结构，从而在遍在蛋白化反应期间SPRY和RBCC元件的结构偶联;以及通过在病毒感染期间促进E3连接酶的亚细胞定位。
TRIM25 is a multi-domain, RING-type E3 ubiquitin ligase of the tripartite motif family that has important roles in multiple RNA-dependent processes. In particular, TRIM25 functions as an effector of RIG-I and ZAP, which are innate immune sensors that recognize viral RNA and induce ubiquitin-dependent anti-viral response mechanisms. TRIM25 is reported to also bind RNA, but the molecular details of this interaction or its relevance to anti-viral defense have not been elucidated. Here, we characterize the RNA-binding activity of TRIM25 and find that the protein binds both single-stranded and double-stranded RNA. Multiple regions of TRIM25 contribute to this functionality, including the C-terminal SPRY domain and a lysine-rich motif in the linker segment connecting the SPRY and coiled-coil domains. RNA binding modulates TRIM25’s ubiquitination activity in vitro, its localization in cells, and its anti-viral activity. Taken together with other studies, our results indicate that RNA binding by TRIM25 has at least three important functional consequences: by enhancing ubiquitination activity, either through allosteric effects or through clustering of multiple TRIM25 molecules; by modulating the multi-domain structure of the TRIM25 dimer, and thereby structural coupling of the SPRY and RBCC elements during the ubiquitination reaction; and by facilitating subcellular localization of the E3 ligase during virus infection.
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