Program in Virology, Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA 02115, USA.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA 02115, USA.
Cell. 2019 May 16;177(5):1187-1200.e16. doi: 10.1016/j.cell.2019.03.017. Epub 2019 Apr 18.
The conventional view posits that E3 ligases function primarily through conjugating ubiquitin (Ub) to their substrate molecules. We report here that RIPLET, an essential E3 ligase in antiviral immunity, promotes the antiviral signaling activity of the viral RNA receptor RIG-I through both Ub-dependent and -independent manners. RIPLET uses its dimeric structure and a bivalent binding mode to preferentially recognize and ubiquitinate RIG-I pre-oligomerized on dsRNA. In addition, RIPLET can cross-bridge RIG-I filaments on longer dsRNAs, inducing aggregate-like RIG-I assemblies. The consequent receptor clustering synergizes with the Ub-dependent mechanism to amplify RIG-I-mediated antiviral signaling in an RNA-length dependent manner. These observations show the unexpected role of an E3 ligase as a co-receptor that directly participates in receptor oligomerization and ligand discrimination. It also highlights a previously unrecognized mechanism by which the innate immune system measures foreign nucleic acid length, a common criterion for self versus non-self nucleic acid discrimination.
传统观点认为 E3 连接酶主要通过将泛素（Ub）连接到其底物分子上来发挥作用。我们在这里报告称，抗病毒免疫中必需的 E3 连接酶 RIPLET 通过依赖 Ub 和不依赖 Ub 的方式促进病毒 RNA 受体 RIG-I 的抗病毒信号活性。RIPLET 使用其二聚体结构和二价结合模式，优先识别和泛素化 dsRNA 上预先寡聚化的 RIG-I。此外，RIPLET 可以在较长的 dsRNA 上交联 RIG-I 纤维，诱导聚集样的 RIG-I 组装。随后的受体聚集与依赖 Ub 的机制协同作用，以 RNA 长度依赖性方式放大 RIG-I 介导的抗病毒信号。这些观察结果表明 E3 连接酶作为共受体的意外作用，其直接参与受体寡聚化和配体识别。它还突出了先天免疫系统测量外源核酸长度的先前未被认识的机制，这是自身与非自身核酸区分的常见标准。
