title: Kaposi's Sarcoma-Associated Herpesvirus Reduces Cellular Myeloid Differentiation Primary-Response Gene 88 (MyD88) Expression via Modulation of Its RNA.
abstract: Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is a human gammaherpesvirus associated with several human malignancies. The replication and transcription activator (RTA) is necessary and sufficient for the switch from KSHV latency to lytic replication. Interleukin 1 (IL-1) is a major mediator for inflammation and plays an important role in both innate and adaptive immunity. Myeloid differentiation primary response gene 88 (MyD88) is an essential adaptor molecule for IL-1 as well as most Toll-like receptor signaling. In this study, we identified a novel mechanism by which KSHV interferes with host inflammation and immunity. KSHV RTA specifically reduces the steady-state protein levels of MyD88, and physiological levels of MyD88 are downregulated during KSHV lytic replication when RTA is expressed. The N-terminal region of RTA is required for the reduction of MyD88. Additional studies demonstrated that RTA targets MyD88 expression at the RNA level, inhibits RNA synthesis of MyD88, and may bind MyD88 RNA. Finally, RTA inhibits IL-1-mediated activation of NF-κB. Because IL-1 is abundant in the KS microenvironment and inhibits KSHV replication, this work may expand our understanding of how KSHV evades host inflammation and immunity for its survival in vivo.
  
  
  OBJECTIVE
  MyD88 is an important molecule for IL-1-mediated inflammation and Toll-like receptor (TLR) signaling. This work shows that KSHV inhibits MyD88 expression through a novel mechanism. KSHV RTA may bind to MyD88 RNA, suppresses RNA synthesis of MyD88, and inhibits IL-1-mediated signaling. This work may expand our understanding of how KSHV evades host inflammation and immunity.
authors.affiliation: School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Lingel
authors.affiliation: School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Ehlers
authors.affiliation: School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, USA.
authors.forename: Qianli
authors.initials: Q
authors.lastname: Wang
authors.affiliation: School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, USA.
authors.forename: Mingxia
authors.initials: M
authors.lastname: Cao
authors.affiliation: School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, USA Nebraska Center for Virology, University of Nebraska, Lincoln, Nebraska, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Wood
authors.affiliation: Lady Davis Institute for Medical Research, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Rongtuan
authors.initials: R
authors.lastname: Lin
authors.affiliation: School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, USA Nebraska Center for Virology, University of Nebraska, Lincoln, Nebraska, USA lzhang2@unl.edu.
authors.forename: Luwen
authors.initials: L
authors.lastname: Zhang
mesh_terms: D002460:Cell Line; D015536:Down-Regulation; D019288:Herpesvirus 8, Human / Q000276:immunology* / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D057131:Immune Evasion; D007375:Interleukin-1 / Q000037:antagonists & inhibitors; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D012333:RNA, Messenger / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D017874:Immediate-Early Proteins; D007375:Interleukin-1; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D012333:RNA, Messenger; C417604:Rta protein, Human herpesvirus 8; D015534:Trans-Activators