2. Academic Validation
  3. Ubiquitin-Dependent and -Independent Roles of E3 Ligase RIPLET in Innate Immunity

Ubiquitin-Dependent and -Independent Roles of E3 Ligase RIPLET in Innate Immunity

  • Cell. 2019 May 16;177(5):1187-1200.e16. doi: 10.1016/j.cell.2019.03.017.
Cristhian Cadena 1,  Sadeem Ahmad 2,  Audrey Xavier 3,  Joschka Willemsen 4,  Sehoon Park 5,  Ji Woo Park 6,  Seong-Wook Oh 7,  Takashi Fujita 7,  Fajian Hou 8,  Marco Binder 4,  Sun Hur 9
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA 02115, USA; Institute of Chemistry and Biochemistry, Free University of Berlin, Germany.
  • 4 Research Group "Dynamics of Early Viral Infection and the Innate Antiviral Response" (division F170), German Cancer Research Center, 69120 Heidelberg, Germany.
  • 5 Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA 02115, USA.
  • 6 Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA 02115, USA; Biology Department, Boston College, Chestnut Hill, MA, USA.
  • 7 Laboratory of Molecular Genetics, Institute for Frontier Life and Medical Sciences, Kyoto University, Japan.
  • 8 State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, China.
  • 9 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. Electronic address: Sun.Hur@childrens.harvard.edu.
PMID: 31006531 DOI: 10.1016/j.cell.2019.03.017
Abstract

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.

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