Inhibition of host RLR pathway by virus

The cellular RIG-like receptors (RLR) belong to an innate sensor pathway that recognize RNA virus products and activates cellular antiviral state. Upon viral infection, RIG-I and related RNA helicases, MDA5 and LGP2 recognize viral "foreign" RNA and trigger intracellular signaling events that induce innate immunity, the first line of defense against microbial infection. These sentry proteins initiate a signaling cascade by interacting with the downstream partner MAVS, located to the mitochondria. Downstream signaling, resulting in the production of cytokines and interferons, has been linked to a number of pathways that ultimately activate transcription factors IRF3, IRF7 and NF-kappa-B.

Inhibition by viruses

Many viral antagonists of the signaling cascade leading to interferon production have been identified. The influenza A virus NS1 protein has been shown to inhibit RIG-I through direct interaction, while paramyxovirus V protein binds and inhibits MDA5 to abrogate its signaling actions. Hepatitis viruses A, B and C affect the cascade by impairing MAVS protein. Downstream, cellular IRF3 and IRF7 can be activated by both RLR and TLR pathway, and are targeted by many viruses including Epstein-Barr virus, Ebolaviruses, Rotaviruses or Papillomaviruses.

Comments MAVS is often described as activating IKBKE (IKK-i or IKK epsilon and/or TBK1 kinases that phosphorylates IRF3. Most results suggest that the IKBKE kinase is preferentially activated by RLR when TBK1 would be activated by TLRs and DNA sensors .

There are evidences showing direct activation of ISG (Interferon Stimulated Genes)upon IKBKE activation. IKBKE could activate STAT1-STAT2 to induce this response .

V N Z NS2 NS1 TRIM25 RIGI RIGI MDA5 M GN LMP1 ABC HBX NS3 MAVS TRAF3 MAVS IF16 zbp1 P NS3 VP35 e6 NSp1 LANA NPRO NSp1 icp0 IKKe TBK1 DDX3 orf45 K7 BZlF1 nsp1 IRF3 STING nsp3 IRF7 VP35 IRF3 IRF1 IRF3 IRF7 IRF3 IRF1