Riplet/RNF135, a RING Finger Protein, Ubiquitinates RIG-I to Promote Interferon-β Induction during the Early Phase of Viral Infection*

By H. Oshiumi, Misako Matsumoto, S. Hatakeyama, Tsukasa Seya. 2009

362 citations recorded by the source corpus.

RIG-I (retinoic acid-inducible gene-I), a cytoplasmic RNA helicase, interacts with IPS-1/MAVS/Cardif/VISA, a protein on the outer membrane of mitochondria, to signal the presence of virus-derived RNA and induce type I interferon production. Activation of RIG-I requires the ubiquitin ligase, TRIM25, which mediates lysine 63-linked polyubiquitination of the RIG-I N-terminal CARD-like region. However, how this modification proceeds for activation of IPS-1 by RIG-I remains unclear. Here we identify an alternative factor, Riplet/RNF135, that promotes RIG-I activation independent of TRIM25. The Riplet/RNF135 protein consists of an N-terminal RING finger domain, C-terminal SPRY and PRY motifs, and shows sequence similarity to TRIM25. Immunoprecipitation analyses demonstrated that the C-terminal helicase and repressor domains of RIG-I interact with the Riplet/RNF135 C-terminal region, whereas the CARD-like region of RIG-I is dispensable for this interaction. Riplet/RNF135 promotes lysine 63-linked polyubiquitination of the C-terminal region of RIG-I, modification of which differs from the N-terminal ubiquitination by TRIM25. Overexpression and knockdown analyses revealed that Riplet/RNF135 promotes RIG-I-mediated interferon-β promoter activation and inhibits propagation of the negative-strand RNA virus, vesicular stomatitis virus. Our data suggest that Riplet/RNF135 is a novel factor of the RIG-I pathway that is involved in the evoking of human innate immunity against RNA virus infection, and activates RIG-I through ubiquitination of its C-terminal region. We infer that a variety of RIG-I-ubiquitinating molecular complexes sustain RIG-I activation to modulate RNA virus replication in the cytoplasm.

Subfields: Immunology, Molecular Biology

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In Immunology

1. Wenshuai Wang
2. Anna Marie Pyle
3. Y. Loo
4. M. Gale
5. Shizuo Akira
6. O. Takeuchi
7. David C. Rawling

In Molecular Biology

1. Wenshuai Wang
2. Anna Marie Pyle
3. Wenyi Wei
4. Lei Chen
5. M. Gale
6. T. Meng
7. Ping Wang
8. Lu Deng

Citations in the corpus

• The RIG-I receptor adopts two different conformations for distinguishing host from viral RNA ligands (2022, background): “…Cell 82, 1–14, November 3, 2022 11 binding of cofactor proteins such asRiplet, are likely to amplify the effects reported here by trapping theCARDs-out state and/or preventing reassociation of the CARDs, thereby forcing the signaling cascade in a forward direction (Oshiumi et al., 2009).”
• The role of ubiquitination in tumorigenesis and targeted drug discovery (2020, background): “Similar to Trim25, RNF135 (also known as Riplet) also catalyzes the K63 polyubiquitination of RIG-I and activates the RIG-I signaling pathway.(248) Additionally, the E3 ligase MIB1/2 regulates the activation of TANK-binding kinase 1 (TBK1) by catalyzing TBK1 K63-linked polyubiquitination.”
• Immune signaling by RIG-I-like receptors (2011, background): “RING finger protein leading to RIG-I activation or Riplet, otherwise known as RNF135 or REUL, is an ubiquitin ligase that interacts with RIG-I but not MDA5 (Gao et al., 2009; Oshiumi et al., 2009).”