REUL is a novel E3 ubiquitin ligase and stimulator of retinoic-acid-inducible gene-I.
RIG-I and MDA5 are cytoplasmic sensors that recognize different species of viral RNAs, leads to activation of the transcription factors IRF3 and NF-kappaB, which collaborate to induce type I interferons. In this study, we identified REUL, a RING-finger protein, as a specific RIG-I-interacting protein. REUL was associated with RIG-I, but not MDA5, through its PRY and SPRY domains. Overexpression of REUL potently potentiated RIG-I-, but not MDA5-mediated downstream signalling and antiviral activity. In contrast, the RING domain deletion mutant of REUL suppressed Sendai virus (SV)-induced, but not cytoplasmic polyI:C-induced activation of IFN-beta promoter. Knockdown of endogenous REUL by RNAi inhibited SV-triggered IFN-beta expression, and also increased VSV replication. Full-length RIG-I, but not the CARD domain deletion mutant of RIG-I, underwent ubiquitination induced by REUL. The Lys 154, 164, and 172 residues of the RIG-I CARD domain were critical for efficient REUL-mediated ubiquitination, as well as the ability of RIG-I to induce activation of IFN-beta promoter. These findings suggest that REUL is an E3 ubiquitin ligase of RIG-I and specifically stimulates RIG-I-mediated innate antiviral activity.
Gao
Dong
D
Key Laboratory of Cell Proliferation and Differentiation (Ministry of Education), College of Life Sciences, Peking University, Beijing, China.
Yang
Yong-Kang
YK
Wang
Rui-Peng
RP
Zhou
Xiang
X
Diao
Fei-Ci
FC
Li
Min-Dian
MD
Zhai
Zhong-He
ZH
Jiang
Zheng-Fan
ZF
Chen
Dan-Ying
DY
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D011971:Receptors, Immunologic; D029082:Sendai virus / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology
D000998:Antiviral Agents; D011971:Receptors, Immunologic; D016899:Interferon-beta; C522809:RNF135 protein, human; D044767:Ubiquitin-Protein Ligases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases