The methyltransferase PRMT6 attenuates antiviral innate immunity by blocking TBK1–IRF3 signaling

Protein arginine methyltransferases(PRMTs)play diverse biological roles and are specifically involved in immune cell development and inflammation.However,their role in antiviral innate immunity has not been elucidated.Viral infection triggers the TBK1–IRF3 signaling pathway to stimulate the production of type-I interferon,which mediates antiviral immunity.We performed a functional screen of the nine mammalian PRMTs for regulators of IFN-βexpression and found that PRMT6 inhibits the antiviral innate immune response.Viral infection also upregulated PRMT6 protein levels.We generated PRMT6-deficient mice and found that they exhibited enhanced antiviral innate immunity.PRMT6 deficiency promoted the TBK1–IRF3 interaction and subsequently enhanced IRF3 activation and type-I interferon production.Mechanistically,viral infection enhanced the binding of PRMT6 to IRF3 and inhibited the interaction between IRF3 and TBK1;this mechanism was independent of PRMT6 methyltransferase activity.Thus,PRMT6 inhibits antiviral innate immunity by sequestering IRF3,thereby blocking TBK1-IRF3 signaling.Our work demonstrates a methyltransferase-independent role for PRMTs.It also identifies a negative regulator of the antiviral immune response,which may protect the host from the damaging effects of an overactive immune system and/or be exploited by viruses to escape immune detection.

Regulation of antiviral innate immunity by deubiquitinase CYLD

An antiviral innate immune response involves induction of type I interferons(IFNs)and their subsequent autocrine and paracrine actions,but the underlying regulatory mechanisms are incompletely understood.Here we report that CYLD,a deubiquitinase that specifically digests lysine 63-linked ubiquitin chains,is required for antiviral host defense.Loss of CYLD renders mice considerably more susceptible to infection by vesicular stomatitis virus(VSV).Consistently,CYLD-deficient dendritic cells are more sensitive to VSV infection.This functional defect was not due to lack of type I IFN production but rather because of attenuated IFN receptor signaling.In the absence of CYLD,IFN-b is ineffective in the induction of antiviral genes and protection of cells from viral infection.These findings establish CYLD as a novel regulator of antiviral innate immunity and suggest a role for CYLD in regulating IFN receptor signaling.

OTUD5 promotes innate antiviral and antitumor immunity through deubiquitinating and stabilizing STING

Stimulator of interferon genes(STING)is an adaptor protein that is critical for effective innate antiviral and antitumor immunity.The activity of STING is heavily regulated by protein ubiquitination,which is fine-tuned by both E3 ubiquitin ligases and deubiquitinases.Here,we report that the deubiquitinase OTUD5 interacts with STING,cleaves its K48-linked polyubiquitin chains,and promotes its stability.Consistently,knockout of OTUD5 resulted in faster turnover of STING and subsequently impaired type I IFN signaling following cytosolic DNA stimulation.More importantly,Lyz2-Cre Otud5^(fl/Y) mice and CD11-Cre Otud5^(fl/Y) mice showed more susceptibility to herpes simplex virus type 1(HSV-1)infection and faster development of melanomas than their corresponding control littermates,indicating that OTUD5 is indispensable for STING-mediated antiviral and antitumor immunity.Our data suggest that OTUD5 is a novel checkpoint in the cGAS-STING cytosolic DNA sensing pathway.

The RNA helicase DDX46 inhibits innate immunity by entrapping m^6 A-demethylated antiviral transcripts in the nucleus

With the support by the National Natural Science Foundation of China,the research team directed by Prof.Cao Xuetao(曹雪涛)at the National Key Laboratory of Medical Molecular Biology&Department of Immunology,Chinese Academy of Medical Sciences,and the National Key Laboratory of Medical Immunology,Second Military Medical University,recently reported that RNA helicase DDX46is