Inhibition of ATF4 transcriptional activity by FIAT/gamma-taxilin modulates bone mass accrual.
The basic domain-leucine zipper protein, activating transcription factor 4 (ATF4), was recently shown to control key aspects of osteoblast biology. ATF4 regulates the timely onset of osteoblast differentiation, the synthesis of type I collagen, and the transcription of the osteocalcin and RANKL (receptor activator of NFkappa-B ligand) genes. Accordingly, the levels and activity of ATF4 are under tight control through mechanisms that include protein stability and phosphorylation. We have uncovered yet another mode of inhibition of ATF4 through its interaction with the leucine zipper protein FIAT (Factor Inhibiting ATF4-mediated Transcription, also described as gamma-taxilin). FIAT/gamma-taxilin localizes to the nucleus in osteoblasts and dimerizes with ATF4 to form inactive dimers, because it does not contain a DNA-binding basic domain moiety. The interaction of FIAT/gamma-taxilin with ATF4 thus inhibits ATF4-mediated transcription. Transgenic mice overexpressing FIAT/gamma-taxilin show osteopenia and reduced expression of the ATF4 target gene, osteocalcin. Interestingly, FIAT/gamma-taxilin also interacts with the transcriptional co-activator alphaNAC (Nascent polypeptide associated complex And Coactivator alpha), suggesting alternative, non-mutually exclusive mechanisms contributing to the inhibition of ATF4-dependent osteocalcin gene transcription by FIAT/gamma-taxilin.
Yu
Vionnie W C
VW
Genetics Unit, Shriners Hospital for Children, 1529 Cedar Avenue, Montreal (Quebec), Canada H3G 1A6.
Gauthier
Claude
C
St-Arnaud
René
R
D051701:Activating Transcription Factor 4 / Q000037:antagonists & inhibitors*; D000818:Animals; D015519:Bone Density / Q000502:physiology*; D001862:Bone Resorption / Q000235:genetics; D002352:Carrier Proteins / Q000502:physiology*; D002455:Cell Division; D056970:Co-Repressor Proteins; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009687:Nuclear Proteins / Q000502:physiology*; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000502:physiology; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000502:physiology*
D002352:Carrier Proteins; D056970:Co-Repressor Proteins; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C488100:TXLNA protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; C502605:Txlng protein, mouse; D033921:Vesicular Transport Proteins; D051701:Activating Transcription Factor 4