Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China.
Mol Cell. 2021 Feb 4;81(3):599-613.e8. doi: 10.1016/j.molcel.2020.11.047. Epub 2020 Dec 28.
RNA helicases and E3 ubiquitin ligases mediate many critical functions in cells, but their actions have largely been studied in distinct biological contexts. Here, we uncover evolutionarily conserved rules of engagement between RNA helicases and tripartite motif (TRIM) E3 ligases that lead to their functional coordination in vertebrate innate immunity. Using cryoelectron microscopy and biochemistry, we show that RIG-I-like receptors (RLRs), viral RNA receptors with helicase domains, interact with their cognate TRIM/TRIM-like E3 ligases through similar epitopes in the helicase domains. Their interactions are avidity driven, restricting the actions of TRIM/TRIM-like proteins and consequent immune activation to RLR multimers. Mass spectrometry and phylogeny-guided biochemical analyses further reveal that similar rules of engagement may apply to diverse RNA helicases and TRIM/TRIM-like proteins. Our analyses suggest not only conserved substrates for TRIM proteins but also, unexpectedly, deep evolutionary connections between TRIM proteins and RNA helicases, linking ubiquitin and RNA biology throughout animal evolution.
RNA 解旋酶和 E3 泛素连接酶在细胞中介导许多关键功能，但它们的作用在很大程度上是在不同的生物学背景下研究的。在这里，我们揭示了 RNA 解旋酶和三联基序（TRIM）E3 连接酶之间的进化保守结合规则，这些规则导致它们在脊椎动物先天免疫中的功能协调。使用冷冻电子显微镜和生物化学方法，我们表明 RIG-I 样受体（RLR），具有解旋酶结构域的病毒 RNA 受体，通过解旋酶结构域中的类似表位与它们的同源 TRIM/TRIM 样 E3 连接酶相互作用。它们的相互作用是亲和力驱动的，将 TRIM/TRIM 样蛋白的作用和随后的免疫激活限制在 RLR 多聚体上。质谱和系统发育引导的生化分析进一步表明，类似的结合规则可能适用于不同的 RNA 解旋酶和 TRIM/TRIM 样蛋白。我们的分析不仅表明了 TRIM 蛋白的保守底物，而且出人意料地表明了 TRIM 蛋白和 RNA 解旋酶之间的深层进化联系，将泛素和 RNA 生物学联系在一起，贯穿整个动物进化。
