Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125

K Arimoto, H Takahashi, T Hishiki… - Proceedings of the …, 2007 - National Acad Sciences
K Arimoto, H Takahashi, T Hishiki, H Konishi, T Fujita, K Shimotohno
Proceedings of the National Academy of Sciences, 2007National Acad Sciences
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 …
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.
National Acad Sciences