The interferon (IFN) Signaling Pathway is the main component of innate immunity and plays an important role in the host’s resistance to pathogens; the production of IFN and the activation of downstream pathways are precisely regulated. The transcription factor STAT1 is a key effector of the IFN pathway. When the IFN signaling pathway is activated, the STAT1 protein is phosphorylated and modified by its kinase JAK1 to form heterologous or homodimers and transfer into the nucleus to regulate the transcriptional activation of downstream target genes. RNF220 is a member of the RING ubiquitin ligase family. Mao Bingyu’s group at the Kunming Institute of Zoology, the Chinese Academy of Sciences revealed that the ubiquitin ligase RNF220 is involved in the development of the vertebrate nervous system and progression of related diseases by mediating different target proteins and different types of ubiquitination modifications. (Ma et al. 2019, Cell Reports; Ma et al. 2020, Development; Song et al. 2020, Development). However, the function and mechanism of RNF220 in other systems, especially in innate immunity and host resistance to infection, are still unclear.
The research groups of the Kunming Institute of Zoology have jointly discovered that exogenous bacterial infection and IFN stimulation induce the expression of endogenous Rnf220 gene in host cells. The results of biochemical experiments showed that the ubiquitin ligase RNF220 interacted with the STAT1 protein and catalyzed the K63 polyubiquitination modification at multiple lysine sites on the STAT1 protein sequence. The study further found that this post-translational modification promotes the interaction between STAT1 and its kinase JAK1, enhances the level of phosphorylation modification of STAT1 protein, and promotes the activation of the IFN-STAT1 signaling pathway. At the same time, the activation of the IFN-STAT1 signaling pathway in Rnf220-deficient cells is inhibited. Rnf220-deficient mice are more susceptible to Acinetobacter baumannii and HSV-1 virus than wild-type mice. This study revealed the molecular mechanism of ubiquitin ligase RNF220 positive feedback regulating the IFN-STAT1 signaling pathway, indicating that RNF220 is expected to become a potential therapeutic target against foreign bacterial and viral infections.
Reference
Ning-Ning Song, Pengcheng Ma, Qiong Zhang, et al. Rnf220/Zc4h2-mediated monoubiquitylation of Phox2 is required for noradrenergic neuron development.
