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

Tom70 mediates activation of interferon regulatory factor 3 on mitochondria

Intracellular RNA viruses are sensed by receptors retinoic acid-inducible gene 1 （RIG-I）/melanoma differentiation-associated gene 5 （MDA5） that trigger the formation of MAVS signal complex on mitochondria. Consequently, this leads to the activation of TANK-binding kinase 1 （TBK1） and phosphorylation of interferon regulatory factor 3 （IRF3）, both of which constitutively associate with cytosolic chaperone Hsp90. It remains largely unknown how MAVS activates TBK1/IRF3. In this study, we identified translocases of outer membrane 70 （Tom70）, a mitochondrial import receptor, to interact with MAVS upon RNA virus infection. Ectopic expression or knockdown of Tom70 could enhance or impair IRF3-mediated gene expression, respectively. Mechanistically, the clamp domain （R192） of Tom70 interacts with the C-terminal motif （EEVD） of Hsp90, thus recruiting TBK1/IRF3 to mitochondria. Disruption of this interaction or mislocation of Tom70 sharply impairs activation of TBK1 and IRF3. Furthermore, host antiviral responses are significantly boosted or crippled in the presence or absence of Tom70. Collectively, our study characterizes Tom70 as a critical adaptor linking MAVS to TBK1/IRF3, revealing that mitochondrion is evolutionarily integrated with innate immunity.

A molecular arms race between host innate antiviral response and emerging human coronaviruses

Coronaviruses have been closely related with mankind for thousands of years. Communityacquired human coronaviruses have long been recognized to cause common cold. However,zoonotic coronaviruses are now becoming more a global concern with the discovery of highly pathogenic severe acute respiratory syndrome(SARS) and Middle East respiratory syndrome(MERS) coronaviruses causing severe respiratory diseases. Infections by these emerging human coronaviruses are characterized by less robust interferon production. Treatment of patients with recombinant interferon regimen promises beneficial outcomes, suggesting that compromised interferon expression might contribute at least partially to the severity of disease. The mechanisms by which coronaviruses evade host innate antiviral response are under intense investigations. This review focuses on the fierce arms race between host innate antiviral immunity and emerging human coronaviruses. Particularly, the host pathogen recognition receptors and the signal transduction pathways to mount an effective antiviral response against SARS and MERS coronavirus infection are discussed. On the other hand, the counter-measures evolved by SARS and MERS coronaviruses to circumvent host defense are also dissected. With a better understanding of the dynamic interaction between host and coronaviruses, it is hoped that insights on the pathogenesis of newly-identified highly pathogenic human coronaviruses and new strategies in antiviral development can be derived.

Gene expression profiles in peripheral blood mononuclear cells of SARS patients

AIM： To investigate the role of inflammatory and anti-vira genes in the pathogenesis of SARS. METHODS： cDNA microarrays were used to screen the gene expression profiles of peripheral blood mononuclear cells （PBMCs） in two SARS patients （one in the acute severe phase and the other in the convalescent phase） and a healthy donor. In addition, real-time qualitative PCR was also performed to verify the reproducibility of the microarray results. The data were further analyzed. RESULTS： Many inflammatory and anti-viral genes were differentially expressed in SARS patients. Compared to the healthy control or the convalescent case, plenty of pro-inflammatory cytokines such as IL-1, TNF-α, IL-8, and MAPK signaling pathway were significantly upregulated in the acute severe case. However, anti-inflammatory agents such as IL-4 receptor, IL-13 receptor, IL-1Ra, and TNF-α-induced proteins 3 and 6 also increased dramatically in the acute severe case. On the contrary, a lot of IFN-stimulated genes like PKR, GBP-1 and 2, CXCL-10 and 11, and JAK/STAT signal pathway were downregulated in the acute severe case compared to the convalescent case. CONCLUSION： Gene expression in SAPS patients mirrors a host state of inflammation and anti-viral immunity at the transcription level, and understanding of gene expression profiles may make contribution to further studies of the SAPS pathogenesis.