title: Daxx mediates activation-induced cell death in microglia by triggering MST1 signalling.
abstract: Microglia, the resident macrophages of the mammalian central nervous system, migrate to sites of tissue damage or infection and become activated. Although the persistent secretion of inflammatory mediators by the activated cells contributes to the pathogenesis of various neurological disorders, most activated microglia eventually undergo apoptosis through the process of activation-induced cell death (AICD). The molecular mechanism of AICD, however, has remained unclear. Here, we show that Daxx and mammalian Ste20-like kinase-1 (MST1) mediate apoptosis elicited by interferon-γ (IFN-γ) in microglia. IFN-γ upregulated the expression of Daxx, which in turn mediated the homodimerization, activation, and nuclear translocation of MST1 and apoptosis in microglial cells. Depletion of Daxx or MST1 by RNA interference also attenuated IFN-γ-induced cell death in primary rat microglia. Furthermore, the extent of IFN-γ-induced death of microglia in the brain of MST1-null mice was significantly reduced compared with that apparent in wild-type mice. Our results thus highlight new functions of Daxx and MST1 that they are the key mediators of microglial cell death initiated by the proinflammatory cytokine IFN-γ.
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
authors.forename: Hee Jae
authors.initials: HJ
authors.lastname: Yun
authors.forename: Je-Hyun
authors.initials: JH
authors.lastname: Yoon
authors.forename: Jae Keun
authors.initials: JK
authors.lastname: Lee
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Noh
authors.forename: Kyoung-Wan
authors.initials: KW
authors.lastname: Yoon
authors.forename: Sang Phil
authors.initials: SP
authors.lastname: Oh
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Oh
authors.forename: Ji Soo
authors.initials: JS
authors.lastname: Chae
authors.forename: Sang Gil
authors.initials: SG
authors.lastname: Hwang
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Kim
authors.forename: Gerd G
authors.initials: GG
authors.lastname: Maul
authors.forename: Dae-Sik
authors.initials: DS
authors.lastname: Lim
authors.forename: Eui-Ju
authors.initials: EJ
authors.lastname: Choi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D016923:Cell Death / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D056970:Co-Repressor Proteins; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D057809:HEK293 Cells; D006367:HeLa Cells; D017228:Hepatocyte Growth Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators; D007371:Interferon-gamma / Q000008:administration & dosage / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology* / Q000502:physiology*; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C491473:Daxx protein, mouse; C528558:Daxx protein, rat; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D007371:Interferon-gamma