title: Kaposi sarcoma-associated herpesvirus degrades cellular Toll-interleukin-1 receptor domain-containing adaptor-inducing beta-interferon (TRIF).
abstract: Kaposi sarcoma-associated herpesvirus (KSHV) is a human γ-herpesvirus associated with several human malignancies. The replication and transcription activator (RTA) is necessary and sufficient for the switch from KSHV latency to lytic replication. Toll-interleukin-1 receptor (TIR) domain-containing adaptor-inducing β-interferon (TRIF, also called TIR-domain-containing adaptor molecule-1 (TICAM-1)) is a signaling adaptor molecule that is critically involved in the Toll-like receptor 3 (TLR-3) and TLR-4 signaling pathways for type I interferon (IFN) production, a key component of innate immunity against microbial infection. In this report, we find a new mechanism by which RTA blocks innate immunity by targeting cellular TRIF. RTA specifically degrades TRIF by shortening the half-life of TRIF protein. This RTA-mediated degradation is at least partially mediated through the ubiquitin-proteasome pathway because proteasome inhibitors as well as knockdown of cellular ubiquitin expression alleviate the degradation. RTA may not directly interact with TRIF and may activate TRIF degradation indirectly through an unknown mediator(s). RTA targets multiple regions of TRIF and may use its ubiquitin ligase domain for the degradation. In addition, physiological levels of TRIF protein are down-regulated during KSHV lytic replication when RTA is expressed. Finally, RTA down-regulates double-stranded RNA-initiated activation of TLR-3 pathway, in the absence of degradation of IFN regulatory factor 7 (IRF-7). Taken together, these data suggest that KSHV employs a novel mechanism to block the innate immunity by degrading TRIF protein. This work may contribute to our understandings on how KSHV evades host immunity for its survival in vivo.
authors.affiliation: From the School of Biological Sciences and.
authors.forename: Humera
authors.initials: H
authors.lastname: Ahmad
authors.affiliation: From the School of Biological Sciences and.
authors.forename: Rachel
authors.initials: R
authors.lastname: Gubbels
authors.affiliation: From the School of Biological Sciences and.
authors.forename: Erica
authors.initials: E
authors.lastname: Ehlers
authors.affiliation: From the School of Biological Sciences and.
authors.forename: Florencia
authors.initials: F
authors.lastname: Meyer
authors.affiliation: From the School of Biological Sciences and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Waterbury
authors.affiliation: the Lady Davis Institute for Medical Research, Department of Medicine, McGill University, Montreal, Quebec H3A 2T5, Canada.
authors.forename: Rongtuan
authors.initials: R
authors.lastname: Lin
authors.affiliation: From the School of Biological Sciences and; Nebraska Center for Virology, University of Nebraska, Lincoln, Nebraska 68588 and. Electronic address: lzhang2@unlnotes.unl.edu.
authors.forename: Luwen
authors.initials: L
authors.lastname: Zhang
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation / Q000276:immunology; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D057131:Immune Evasion / Q000276:immunology; D007113:Immunity, Innate; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012330:RNA, Double-Stranded / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017735:Virus Latency / Q000502:physiology; D014779:Virus Replication / Q000502:physiology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C494234:IRF7 protein, human; D017874:Immediate-Early Proteins; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D012330:RNA, Double-Stranded; C417604:Rta protein, Human herpesvirus 8; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D015534:Trans-Activators; D025801:Ubiquitin; D014764:Viral Proteins; D046988:Proteasome Endopeptidase Complex