Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125.
Retinoic acid-inducible gene I (RIG-I) plays a pivotal role in the regulation of cytokine production induced by pathogens. The RIG-I also augments the production of IFN and other cytokines via an amplification circuit. Because the production of cytokines is closely controlled, up- and down-regulation of RIG-I signaling also needs strict regulation. The mechanism of this regulation, however, remains elusive. Here, we found that RIG-I undergoes proteasomal degradation after conjugation to ubiquitin by RNF125. Further, RNF125 conjugates ubiquitin to MDA5, a family protein of RIG-I as well as IPS-1, which is also a downstream protein of RIG-I signaling that results in suppressing the functions of these proteins. Because RNF125 is enhanced by IFN, these functions constitute a negative regulatory loop circuit for IFN production.
Arimoto
Kei-ichiro
K
Department of Viral Oncology, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
Takahashi
Hitoshi
H
Hishiki
Takayuki
T
Konishi
Hideyuki
H
Fujita
Takashi
T
Shimotohno
Kunitada
K
D000818:Animals; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology; D051379:Mice; D011070:Poly I-C / Q000494:pharmacology; D011485:Protein Binding; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; D025801:Ubiquitin; C471622:UBE2L6 protein, human; D044763:Ubiquitin-Conjugating Enzymes; C000603471:RNF125 protein, mouse; D044767:Ubiquitin-Protein Ligases; D053487:DEAD-box RNA Helicases; D011070:Poly I-C