Targeting m6A modification inhibits herpes virus 1 infection

The latent infection by herpes virus type 1(HSV-1)may be lifelong in trigeminal ganglia and a suspected cause of Alzheimer's Disease(AD)and Amyotrophic lateral sclerosis(ALS).Whether and how N6-methyladenosine(m6A)modification of viral RNAs affects virus infection are poorly understood.Here,we report that HSV-1 infection enhanced the expression of m6A writers(METTL3,METTL14)and readers(YTHDF1/2/3)at the early infection stage and decreased their expression later on,while suppressed the erasers'(FTO,ALBKH5)expression immediately upon infection to facilitate viral replication.Inhibiting m6A modification by 3-deazaadenosine(DAA)significantly decreased viral replication and reduced viral reproduction over 1000 folds.More interestingly,depleting the writers and readers by siRNAs inhibited virus replication and reproduction;whereas depleting the erasers promoted viral replication and reproduction.Silencing YTHDF3 strikingly decreased viral replication by up to 90%,leading to reduction of up to 10-fold viral replication and over 100-fold virus reproduction,respectively.Depletion of m6A initiator METTL3(by 60%–70%)by siRNA correlatedly decreased viral replication 60%–70%,and reduced virus yield over 30-fold.Consistently,ectopic expression of METTL3 largely increased virus yield.METTL3 knockdown suppressed the HSV-1 intermediate early and early genes(ICP0,ICP8 and UL23)and late genes(VP16,UL44,UL49 and ICP47);while ectopic expression of METTL3 upregulated these gene expression.Results from our study shed the lights on the importance for m6A modification to initiate HSV-1 early replication.The components of m6A modification machinery,particularly m6A initiator METTL3 and reader YTHDF3,would be potential important targets for combating HSV-1 infections.

Novel HDAC5-interacting motifs of Tbx3 are essential for the suppression of E-cadherin expression and for the promotion of metastasis in hepatocellular carcinoma

Tbx3,a transcriptional repressor,is essential in the organogenesis of vertebrates,stem cell self-renewal and differentiation,and the carcinogenesis of multiple tumor types.However,the mechanism by which Tbx3 participates in the metastasis of hepatocellular carcinoma(HCC)remains largely unknown.In this study,we show that Tbx3 was dramatically upregulated in clinical HCC samples and that elevated expression of Tbx3 promoted cancer progression.To determine the underlying mechanism,systematic glycine scan mutagenesis and deletion assays were performed.We identified two critical motifs,^(585)LFSYPYT^(591)and^(604)HRH^(606),that contribute to the repression of transcriptional activity.These motifs are also essential for Tbx3 to promote cell migration and metastasis both in vitro and in vivo via the suppression of E-cadherin expression.More importantly,Tbx3 directly interacts with HDAC5 via these motifs,and an HDAC inhibitor blocks Tbx3-mediated cell migration and the downregulation of E-cadherin in HCC.As Tbx3 is involved in the carcinogenesis of multiple types of human cancers,our findings suggest an important target for anticancer drug development.

Attenuating innate immunity and facilitating β-coronavirus infection by NSP1 of SARS-CoV-2 through specific redistributing hnRNP A2/B1 cellular localization

Dear Editor,Evidence shows the NSP1’s crucial roles of theβ-coronavirus SARS-CoV-2 in promoting cellular mRNA degradation,inhibiting host cell translation,innate immunity,and inducing inflammatory cytokine storm in the pathogenesis of COVID-19.1,2 More interestingly,NSP1 deletion in infectious clones prevents virus infection.3 However,little is known how NSP1 interacts with host factors to disrupt the host’s innate immunity for facilitating virus infection and reproduction.As a(+)ssRNA virus,SARS-CoV-2 completes its life cycle in the cytosol;viral RNA processing is the key for controlling and regulating the virus reproduction and pathogenesis.The ribonucleoproteins hnRNPs are the main factors responsible for RNA processing,including RNA splicing,maturation,decay,and translation,and even innate immunity in some cases.

PIM1 kinase facilitates Zika virus replication by suppressing host cells’natural immunity

Dear Editors,Oncoprotein PIM1 kinase participates in many important biological processes,such as cell proliferation,apoptosis,carcinogenesis and tumorigenesis,by phosphorylating cellular substrates.More recently,several groups discovered that PIM1 affects(+)ssRNA virus transcription and modulates virus infection,such as human rhinovirus(HRV)-16 and hepatitis C virus(HCV).2 We recently reported that PIM1 enhances EV-A71 IRES activity by regulating AUF1 translocation.