Shandong University’s Han Lihui team discovered for the first time that cGAS can be modified by arginine methylation

iNature cyclic GMP-AMP synthase (cGAS) acts as an essential DNA sensor, which can sense cytoplasmic double-stranded DNA and activate antiviral reactions.

However, the post-translational modification of cGAS remains to be fully understood, and it is still unknown whether it has arginine methylation modification.

On March 24, 2021, Han Lihui’s team from Shandong University published a research paper titled "Arginine methyltransferase PRMT5 negatively regulates cGAS-mediated antiviral immune response" in Science Advances.
The study identified arginine methyltransferase 5 (PRMT5) as The direct binding partner of cGAS, and catalyzes the symmetric dimethylation of arginine at residue Arg124 of cGAS.

Further studies have shown that the methylation of cGAS by PRMT5 can attenuate the cGAS-mediated antiviral immune response by blocking the DNA binding ability of cGAS.

Oral PRMT5 inhibitors can significantly protect mice from HSV-1 infection and prolong the survival time of these infected mice.

Therefore, the findings of this study reveal the important regulatory effect of PRMT5 on the cGAS-mediated antiviral immune response, and provide a promising potential antiviral strategy by regulating PRMT5.

Infectious diseases, especially viral infections, are still a serious threat to mankind.

After infection, eukaryotic cells will immediately respond with a powerful innate immune response as a key defense against invading pathogens.

cGAS is a key cytoplasmic DNA sensor that detects cytoplasmic microbial DNA or its own DNA and induces the production of type I interferon (IFN).

After binding to double-stranded DNA (dsDNA), cGAS synthesizes cGAMP, cGAMP is the second messenger molecule, cGAMP binds to the stimulator of the adaptor protein (STING) of the IFN gene and induces conformational changes in the STING dimer.

The latter induces the activation of TBK1 and the transcription factor IFN regulatory factor 3 (IRF3), which further stimulates the production of type I IFN, and subsequently induces the synthesis of antiviral proteins to effectively defend against pathogens.

Effective activation of cGAS signals is essential to prevent viral infections and diseases.

Therefore, it must be strictly controlled to ensure an effective response to DNA viruses while preventing damage to the immune system.

However, the regulatory mechanism of the cGAS-STING pathway remains to be fully understood.

Several types of post-translational modifications (PTM) have been shown, including phosphorylation, SUMOylation, acetylation, polyubiquitination, monoubiquitination, and glutamylation, which directly or indirectly regulate cGAS-STING-mediated Innate immune response.

Whether cGAS is modified by protein arginine methylation remains to be clarified.

Protein arginine methylation may affect the interaction between protein and DNA, which indicates that it has great potential in regulating the well-known cytoplasmic DNA sensor cGAS.

Arginine methyltransferase (PRMT) in mammals catalyzes the methylation of arginine, a common PTM that participates in a variety of biological processes, including cell signal transduction, RNA processing, and chromatin remodeling And DNA repair mediated by homologous recombination.

PRMT is divided into three types: Type I PRMT (PRMT1, PRMT2, PRMT3, PRMT4 / CARM1, PRMT6 and PRMT8), which will generate asymmetric dimethyl arginine; Type II PRMT (PRMT5 and PRMT9), which can Produce symmetric dimethyl arginine; Type III PRMT (PRMT7), can produce monomethylated arginine.

Through mass spectrometry analysis of cGAS-interacting proteins, PRMT5 was identified as a potential candidate binding protein for cGAS.

PRMT5 is the major type II arginine methyltransferase, which can symmetrically methylate arginine residues and usually forms a complex with the cofactor MEP50.

The deletion of PRMT5 is embryonic lethal in mice because it is essential for the proliferation and differentiation of several stem cell lineages.

The role of PRMT5 has been reported in a number of biological processes, especially in immune-related processes, including maintaining T cell development and T helper 17 (TH17) cell differentiation, regulating CD4 + T cell expansion, and inducing T cells.
IFN signal transduction in cells regulates B cell function and antibody production, maintains normal hematopoietic function and regulates cell cycle progression.

The regulatory role of PRMT5 has been defined in a variety of signal transduction processes, including nuclear factor kappa B (NF-κB) signal transduction, phosphatidylinositol 3-kinase (PI3K)-AKT pathway, IFN signal transduction and WNT / β-catenin pathway.

Although the function of PRMT5 in a variety of biological processes has been extensively studied, its direct modification of cGAS and its regulation of cGAS-mediated immunity against DNA viruses remain to be elucidated.

In this study, the symmetrical arginine methylation of the RGG/RG motif of cGAS by PRMT5 was defined, and its regulatory effect on the innate immune response of DNA viruses was defined.

This study further proved that the methylation of cGAS by PRMT5 can inhibit the DNA binding ability of cGAS and further inhibit the cGAS-mediated antiviral immune response.

These findings provide insights into tightly regulated antiviral immunity and indicate a potential strategy to combat viral infections by regulating PRMT5-induced methylation.

Reference message: https://advances.
sciencemag.
org/content/7/13/eabc1834