Viral hijacking of the host ubiquitin system to evade interferon responses

Host anti-viral signals are initiated when cells sense the presence of pathogens via pattern-recognition receptors (PRRs) such as extracellular toll like receptors (TLRs), or intracellular RIG-I like helicases (RLHs) or DNA binding proteins. PRRs recognize molecular signatures of pathogens, the single or double stranded RNA or DNA. TLR3 activates Toll–interleukin (IL)-1-resistance (TIR) domain-containing adaptor inducing IFN-b (TRIF), whereas TLR7 and 9 activate myeloid differentiation factor 88 (MyD88). Melanoma differentiation– associated gene (mda-5) and retinoic acid-inducible gene-1 (RIG-I) activate tumor necrosis factor (TNF) receptor associated factor 3 (TRAF3) via Cardif/VISA/MAVS/IPS-1. Activated TRAF3 interacts with TRAF family member associated NFκB activator (TANK), TANK binding kinase 1 (TBK-1) and the related IκB Kinase ε (IKKε) to phosphorylate and translocate IRFs in the nucleus. In a parallel pathway, NFκb activation is initiated by polyubiquitination of TRAF6 and receptor interacting protein -1 (RIP1). These adaptors recruit transforming growth factor (TGF) β –activating enzyme 1 (TAK1), NFκB essential modifier (NEMO) and IκB Kinases (IKK) into a multi protein complex that phosphorylates inhibitor of NFκB (IκB) resulting in its ubiquitination and degradation by proteasomes. The degradation of IκB reveals the nuclear localization signal of NFκB which then translocates to the nucleus. In the nucleus, activated IRFs and NFκB assemble at the IFNβ promoter together with ATF-2/c-jun and other co-factors to stimulate IFN transcription. IFNs are secreted and induce an antiviral state in neighboring cells by binding to the receptors IFNAR 1 &2 and activating the tyrosine kinases JAK1 and Tyk2 which in turn activate signal transducer and activator of transcription (STATs). Phosphorylated STAT1 and STAT2 heterodimerize and translocate to the nucleus, where they associate with IRF-9 to form the hetrotrimeric transcription factor ISGF3. Binding of ISGF3 to the IFN stimulated response element (ISRE) induces transcription of IFN stimulated genes (ISGs).Viral intervention of these pathway proteins are marked in the figure as numbers and listed below in the virus (protein)[ref] format :1. Influenza A virus (NS1) []; 2. Measles virus (P) []; 3. African swine fever virus (A238L) [], Rotavirus (NSP1) []; 4.Murid herpesvirus-4 (ORF73) [], Poxvirus (CP77) []; 5. classical swine fever virus [], Bovine viral diarrhea virus [], Rotavirus [,], HIV-1 ( Vpr, Vif) []; 6. Ebola virus (VP35) []; 7. Para influenza simian virus 5 [,]; 8.Respiratory syncytial virus (NS1) []; 9.Hepatitis C virus []; 10. Human cytomegalovirus (US2, US11) [], Kaposi’s Sarcoma associated herpesvirus [KSHV] (K3, K5) [,]; 11. Influenza virus (NS1A) [, –], vaccinia virus (E3) [], Coronavirus (PLP) []; 12. HIV-1 (Vpu) [, , –], KSHV (K5) [].

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Viral hijacking of the host ubiquitin system to evade interferon responses. () Kasinath Viswanathan, et al. Curr Opin Microbiol. ;13(4):517-523. Figure: F1. All organisms Mus musculus Homo sapiens Danio rerio

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