PCBP1 modulates the innate immune response by facilitating the binding of cGAS to DNA

Cyclic GMP-AMP synthase(cGAS)is a key sensor critical for the recognition of DNA in the cytosol and catalyzes the synthesis of the second messenger cyclic GMP-AMP(cGAMP),which binds to the adapter protein MITA(also known as STING,MPYS,and ERIS)to initiate the innate immune response.How the binding of DNA to and the activation of cGAS are regulated remains poorly understood.Using a biochemical purification approach,we identified poly(rC)-binding protein 1(PCBP1)as a cGAS-associated protein.PCBP1 was recruited to cGAS in a viral infection-dependent manner.PCBP1 directly bound to DNA and enhanced cGAS binding to its ligands,which was important for cGAS activation.Consistently,PCBP1 deficiency inhibited cytosolic DNA-and DNA virus-triggered transcription of downstream effector genes.These findings suggest that PCBP1 plays an important role in the cGAS-mediated innate immune response to DNA virus infection by promoting the binding of cGAS to viral DNA.

IFITM3 inhibits virus-triggered induction of type I interferon by mediating autophagosome-dependent degradation of IRF3

Interferon-induced transmembrane protein 3 (IFITM3) is a restriction factor that can be induced by viral infectionand interferons (IFNs). It inhibits the entry and replication of many viruses, which are independent of receptorusage but dependent on processes that occur in endosomes. In this study, we demonstrate that IFITM3 playsimportant roles in regulating the RNA-virus-triggered production of IFN-β in a negative-feedback manner.Overexpression of IFITM3 inhibited Sendai virus-triggered induction of IFN-β, whereas knockdown of IFITM3 hadthe opposite effect. We also showed that IFITM3 was constitutively associated with IRF3 and regulated thehomeostasis of IRF3 by mediating the autophagic degradation of IRF3. These findings suggest a novel inhibitoryfunction of IFITM3 on the RNA-virus-triggered production of type I IFNs and cellular antiviral responses.

The zinc-finger protein ZFYVE1 modulates TLR3-mediated signaling by facilitating TLR3 ligand binding

Recognition of viral dsRNA by Toll-like receptor 3(TLR3)leads to the induction of downstream antiviral effectors and the innate antiviral immune response.Here,we identified the zinc-finger FYVE domain-containing protein ZFYVE1,a guanylate-binding protein(GBP),as a positive regulator of TLR3-mediated signaling.Overexpression of ZFYVE1 promoted the transcription of downstream antiviral genes upon stimulation with the synthetic TLR3 ligand poly(I:C).Conversely,ZFYVE1 deficiency had the opposite effect.Zfyve1^(−/−) mice were less susceptible than wild-type mice to inflammatory death induced by poly(I:C)but not LPS.ZFYVE1 was associated with TLR3,and the FYVE domain of ZFYVE1 and the ectodomain of TLR3 were shown to be responsible for their interaction.ZFYVE1 was bound to poly(I:C)and increased the binding affinity of TLR3 to poly(I:C).These findings suggest that ZFYVE1 plays an important role in the TLR3-mediated innate immune and inflammatory responses by promoting the ligand binding of TLR3.

Heat shock cognate 71 (HSC71) regulates cellular antiviral response by impairing formation of VISA aggregates

In response to viral infection, RIG-I-like RNA helicases detect viral RNA and signal through the mitochondrial adapter protein VISA. VISA activation leads to rapid activation of transcription factors IRF3 and NF-κB, which collaborate to induce transcription of type I interferon (IFN) genes and cellular antiviral response. It has been demonstrated that VISA is activated by forming prion-like aggregates. However, how this process is regulated remains unknown. Here we show that overexpression of HSC71 resulted in potent inhibition of virus-triggered transcription of IFNB1 gene and cellular antiviral response. Consistently, knockdown of HSC71 had opposite effects. HSC71 interacted with VISA, and negatively regulated virus-triggered VISA aggregation. These findings suggest that HSC71 functions as a check against VISA-mediated antiviral response.