title: TLR-TRIF pathway enhances the expression of KSHV replication and transcription activator.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is a human γ-herpesvirus. KSHV replication and transcription activator (RTA) is necessary and sufficient for KSHV reactivation from latency. Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns, act through adaptors, and initiate innate and adaptive immune responses against pathogens. Toll/interleukin-1-receptor domain containing adaptor protein inducing interferon-β (TRIF) is an adaptor associated with TLR3 and TLR4 signaling, and is closely related to antiviral signaling to activate type I interferon (IFN) production. We previously found that KSHV RTA degrades TRIF indirectly and blocks TLR3 pathways. In this report, we find that TRIF, as well as TLR3 activation, enhances KSHV RTA protein expression. The C-terminal region of the RTA is involved in the responding TRIF-mediated enhancement. The degradation of TRIF and the enhancement of RTA expression are using two different pathways. The enhancement by TLR-TRIF is at least partially via promoting translational efficiency of RTA mRNA. Finally, the receptor-interacting protein 1 (RIP1) may be involved in TRIF-mediated enhancement of RTA expression, but not in the RTA-mediated degradation of TRIF. Therefore, the activation of TLR-TRIF pathway enhances KSHV RTA protein expression, and KSHV RTA in turn degrades TRIF to block innate immunity. The putative KSHV-TLR-adaptor-interacting loop may be a critical element to evade and usurp host innate immunity in KSHV life-cycle.
authors.affiliation: School of Biological Sciences, University of Nebraska, Lincoln, Nebraska 68583, USA.
authors.forename: Florencia
authors.initials: F
authors.lastname: Meyer
authors.forename: Erica
authors.initials: E
authors.lastname: Ehlers
authors.forename: Andrew
authors.initials: A
authors.lastname: Steadman
authors.forename: Thomas
authors.initials: T
authors.lastname: Waterbury
authors.forename: Mingxia
authors.initials: M
authors.lastname: Cao
authors.forename: Luwen
authors.initials: L
authors.lastname: Zhang
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D015870:Gene Expression / Q000276:immunology; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009154:Mutation; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
chemical_list: C119724:AGFG1 protein, human; D033942:Adaptor Proteins, Vesicular Transport; D017874:Immediate-Early Proteins; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; C417604:Rta protein, Human herpesvirus 8; C470409:TICAM1 protein, human; D051196:Toll-Like Receptor 3; D015534:Trans-Activators
keywords: Innate Immunity; TRIF; Toll-like Receptors (TLR); Translation Control; Tumor Viruses