title: Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells.
abstract: Human cytomegalovirus (HCMV) infection of the developing fetus frequently results in major neural developmental damage. In previous studies, HCMV was shown to downregulate neural progenitor/stem cell (NPC) markers and induce abnormal differentiation. As Notch signaling plays a vital role in the maintenance of stem cell status and is a switch that governs NPC differentiation, the effect of HCMV infection on the Notch signaling pathway in NPCs was investigated. HCMV downregulated mRNA levels of Notch1 and its ligand, Jag1, and reduced protein levels and altered the intracellular localization of Jag1 and the intracellular effector form of Notch1, NICD1. These effects required HCMV gene expression and appeared to be mediated through enhanced proteasomal degradation. Transient expression of the viral tegument proteins of pp71 and UL26 reduced NICD1 and Jag1 protein levels endogenously and exogenously. Given the critical role of Notch signaling in NPC growth and differentiation, these findings reveal important mechanisms by which HCMV disturbs neural cell development in vitro. Similar events in vivo may be associated with HCMV-mediated neuropathogenesis during congenital infection in the fetal brain.
  
  
  OBJECTIVE
  Congenital human cytomegalovirus (HCMV) infection is the leading cause of birth defects that primarily manifest as neurological disabilities. Neural progenitor cells (NPCs), key players in fetal brain development, are the most susceptible cell type for HCMV infection in the fetal brain. Studies have shown that NPCs are fully permissive for HCMV infection, which causes neural cell loss and premature differentiation, thereby perturbing NPC fate. Elucidation of virus-host interactions that govern NPC proliferation and differentiation is critical to understanding neuropathogenesis. The Notch signaling pathway is critical for maintaining stem cell status and functions as a switch for differentiation of NPCs. Our investigation into the impact of HCMV infection on this pathway revealed that HCMV dysregulates Notch signaling by altering expression of the Notch ligand Jag1, Notch1, and its active effector in NPCs. These results suggest a mechanism for the neuropathogenesis induced by HCMV infection that includes altered NPC differentiation and proliferation.
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Li
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Xi-Juan
authors.initials: XJ
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Ya-Ru
authors.initials: YR
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Zhang-Zhou
authors.initials: ZZ
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Ling-Feng
authors.initials: LF
authors.lastname: Miao
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Simon
authors.initials: S
authors.lastname: Rayner
authors.affiliation: INSERM, U563, Toulouse, France.
authors.forename: Stéphane
authors.identifier: http://orcid.org/0000-0003-4323-2656
authors.initials: S
authors.lastname: Chavanas
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Pediatrics, University of Alabama School of Medicine, Birmingham, Alabama, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Britt
authors.affiliation: Department of Microbiology, Howard University College of Medicine, Washington, DC, USA.
authors.forename: Qiyi
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McVoy
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China luomh@wh.iov.cn.
authors.forename: Min-Hua
authors.initials: MH
authors.lastname: Luo
mesh_terms: D002135:Calcium-Binding Proteins / Q000378:metabolism*; D003586:Cytomegalovirus Infections / Q000473:pathology* / Q000821:virology; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism*; D058953:Neural Stem Cells / Q000502:physiology* / Q000821:virology; D055550:Protein Stability; D059748:Proteolysis; D051881:Receptor, Notch1 / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D014763:Viral Matrix Proteins / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D014763:Viral Matrix Proteins; D014764:Viral Proteins; C047015:cytomegalovirus matrix protein, pp 64-69; C051298:cytomegalovirus phosphoprotein 71kDa