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1.
J Biol Chem ; 292(15): 6076-6085, 2017 04 14.
Article in English | MEDLINE | ID: mdl-28246173

ABSTRACT

Nutrient-driven O-GlcNAcylation is strikingly abundant in the brain and has been linked to development and neurodegenerative disease. We selectively targeted the O-GlcNAcase (Oga) gene in the mouse brain to define the role of O-GlcNAc cycling in the central nervous system. Brain knockout animals exhibited dramatically increased brain O-GlcNAc levels and pleiotropic phenotypes, including early-onset obesity, growth defects, and metabolic dysregulation. Anatomical defects in the Oga knockout included delayed brain differentiation and neurogenesis as well as abnormal proliferation accompanying a developmental delay. The molecular basis for these defects included transcriptional changes accompanying differentiating embryonic stem cells. In Oga KO mouse ES cells, we observed pronounced changes in expression of pluripotency markers, including Sox2, Nanog, and Otx2. These findings link the O-GlcNAc modification to mammalian neurogenesis and highlight the role of this nutrient-sensing pathway in developmental plasticity and metabolic homeostasis.


Subject(s)
Acetylglucosamine/metabolism , Brain/metabolism , Mouse Embryonic Stem Cells/metabolism , N-Acetylglucosaminyltransferases/metabolism , Neurogenesis/physiology , Acetylglucosamine/genetics , Animals , Brain/cytology , Mice , Mice, Knockout , Mouse Embryonic Stem Cells/cytology , N-Acetylglucosaminyltransferases/genetics , Nanog Homeobox Protein/genetics , Nanog Homeobox Protein/metabolism , Organ Specificity/physiology , Otx Transcription Factors/genetics , Otx Transcription Factors/metabolism , SOXB1 Transcription Factors/genetics , SOXB1 Transcription Factors/metabolism
2.
J Biol Chem ; 277(36): 33300-10, 2002 Sep 06.
Article in English | MEDLINE | ID: mdl-12070139

ABSTRACT

This study demonstrates that the steroidogenic acute regulatory protein-related lipid transfer (START) domain-containing protein, MLN64, participates in intracellular cholesterol trafficking. Analysis of the intracellular itinerary of MLN64 and MLN64 mutants tagged with green fluorescent protein showed that the N-terminal transmembrane domains mediate endocytosis of MLN64 from the plasma membrane to late endocytic compartments. MLN64 constitutively traffics via dynamic NPC1-containing late endosomal tubules in normal cells; this dynamic movement was inhibited in cholesterol-loaded cells, and MLN64 is trapped at the periphery of cholesterol-laden lysosomes. The MLN64 START domain stimulated free cholesterol transfer from donor to acceptor mitochondrial membranes and enhanced steroidogenesis by placental mitochondria. Expression of a truncated form of MLN64 (DeltaSTART-MLN64), which contains N-terminal transmembrane domains but lacks the START domain, caused free cholesterol accumulation in lysosomes and inhibited late endocytic dynamics. The DeltaSTART-MLN64 dominant negative protein was located at the surface of the cholesterol-laden lysosomes. This dominant negative mutant suppressed steroidogenesis in COS cells expressing the mitochondrial cholesterol side chain cleavage system. We conclude that MLN64 participates in mobilization and utilization of lysosomal cholesterol by virtue of the START domain's role in cholesterol transport.


Subject(s)
Carrier Proteins , Cell Membrane/metabolism , Lysosomes/metabolism , Membrane Proteins/physiology , Mitochondria/metabolism , Animals , Biological Transport , Blotting, Western , CHO Cells , COS Cells , Cholesterol/metabolism , Cricetinae , Endocytosis , Genes, Dominant , Humans , Immunoblotting , Membrane Proteins/metabolism , Microscopy, Confocal , Microscopy, Fluorescence , Plasmids/metabolism , Progesterone/metabolism , Protein Binding , Protein Structure, Tertiary , Recombinant Fusion Proteins/metabolism , Time Factors , Transfection
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