title: Daxx upregulation within the cytoplasm of reovirus-infected cells is mediated by interferon and contributes to apoptosis.
abstract: Reovirus infection is a well-characterized experimental system for the study of viral pathogenesis and antiviral immunity within the central nervous system (CNS). We have previously shown that c-Jun N-terminal kinase (JNK) and the Fas death receptor each play a role in neuronal apoptosis occurring in reovirus-infected brains. Death-associated protein 6 (Daxx) is a cellular protein that mechanistically links Fas signaling to JNK signaling in several models of apoptosis. In the present study, we demonstrate that Daxx is upregulated in reovirus-infected brain tissue through a type I interferon-mediated mechanism. Daxx upregulation is limited to brain regions that undergo reovirus-induced apoptosis and occurs in the cytoplasm and nucleus of neurons. Cytoplasmic Daxx is present in Fas-expressing cells during reovirus encephalitis, suggesting a role for Daxx in Fas-mediated apoptosis following reovirus infection. Further, in vitro expression of a dominant negative form of Daxx (DN-Daxx), which binds to Fas but which does not transmit downstream signaling, inhibits apoptosis of reovirus-infected cells. In contrast, in vitro depletion of Daxx results in increased expression of caspase 3 and apoptosis, suggesting that Daxx plays an antiapoptotic role in the nucleus. Overall, these data imply a regulatory role for Daxx in reovirus-induced apoptosis, depending on its location in the nucleus or cytoplasm.
authors.affiliation: University of Colorado, Denver, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Kalen R
authors.initials: KR
authors.lastname: Dionne
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Zhuang
authors.forename: J Smith
authors.initials: JS
authors.lastname: Leser
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Tyler
authors.forename: Penny
authors.initials: P
authors.lastname: Clarke
mesh_terms: D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000096:biosynthesis*; D056970:Co-Repressor Proteins; D003593:Cytoplasm / Q000821:virology*; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D012089:Mammalian orthoreovirus 3 / Q000276:immunology / Q000472:pathogenicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones; D009474:Neurons / Q000821:virology*; D009687:Nuclear Proteins / Q000096:biosynthesis*; D015854:Up-Regulation
chemical_list: D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C491473:Daxx protein, mouse; D007370:Interferon Type I; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins