Cao Xuetao’s Team Reported a New Regulatory Mechanism of Antiviral Innate Immunity on Nature Immunology

2017-11-23

Cao Xuetao’s team, from Department of Immunology & Centre for Immunotherapy, Institute of Basic Medical Sciences, demonstrated that E3 ubiquitin ligase RNF2 can induce the occurrence of a new ubiquitination modification in STAT1 (i.e. K33-linked poly-ubiquitination modification) to promote STAT1 dissociated from DNA and inhibit STAT1 transcription, which in turn inhibits the expression of a series of interferon-stimulated genes (ISGs) downstream STAT1 and eventually inhibits the interferon-mediated antiviral natural immune function. Relevant results were published online on November 21 on Nature Immunology.

 

With the support of NSFC Basic Science Research Center project and CAMS Innovation Fund for Medical Sciences, Dr. Liu Shuo and Jiang Minghong from Cao Xuetao’s team used high content screening system to screen the regulation effect of E3 ubiquitin ligase RNF family protein in the antiviral natural immune response, and found that Ring finger protein 2 (RNF2) can negatively regulate type I interferon-mediated antiviral responses. After type I interferon stimulates target cells, it triggers interaction between RNF2 and the DNA binding domain of STAT1. Its E3 ubiquitin ligase activity promotes the occurrence of K33-linked poly-ubiquitination modification in the 379th lysine of STAT1, which promotes the dissociation of STAT1 from its binding DNA and ultimately reduces the expression of downstream ISGs gene. They found that multiple molecules of the RNF family are involved in the regulation of antiviral natural immune response, where the epigenetically regulated protein RNF2 could inhibit the transcription of STAT1 against ISGs independent of its regulation on chromatin and histone. Mice with myeloid cell specifically knocking out RNF2 were more resistant to various viral infections and had an increased expression of antiviral ISGs, further proving the negative regulation of RNF2 participating in the type I interferon signaling pathway and antiviral response.

 

The findings further deepen the understanding of the antiviral natural immune regulatory mechanisms and provide new strategies and potential targets for the treatment and drug development of viral infections and related inflammatory diseases.

 

Link: http://www.nature.com/articles/s41590-017-0003-0#MOESM3

 

 

(Institute of Basic Medical Sciences)