title: A sterol-binding protein integrates endosomal lipid metabolism with TOR signaling and nitrogen sensing.
abstract: Kes1, and other oxysterol-binding protein superfamily members, are involved in membrane and lipid trafficking through trans-Golgi network (TGN) and endosomal systems. We demonstrate that Kes1 represents a sterol-regulated antagonist of TGN/endosomal phosphatidylinositol-4-phosphate signaling. This regulation modulates TOR activation by amino acids and dampens gene expression driven by Gcn4, the primary transcriptional activator of the general amino acid control regulon. Kes1-mediated repression of Gcn4 transcription factor activity is characterized by nonproductive Gcn4 binding to its target sequences, involves TGN/endosome-derived sphingolipid signaling, and requires activity of the cyclin-dependent kinase 8 (CDK8) module of the enigmatic "large Mediator" complex. These data describe a pathway by which Kes1 integrates lipid metabolism with TORC1 signaling and nitrogen sensing.
authors.affiliation: Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7090, USA. mousley@email.unc.edu
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Mousley
authors.forename: Peihua
authors.initials: P
authors.lastname: Yuan
authors.forename: Naseem A
authors.initials: NA
authors.lastname: Gaur
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Trettin
authors.forename: Aaron H
authors.initials: AH
authors.lastname: Nile
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Deminoff
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Dewar
authors.forename: Max
authors.initials: M
authors.lastname: Wolpert
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Macdonald
authors.forename: Paul K
authors.initials: PK
authors.lastname: Herman
authors.forename: Alan G
authors.initials: AG
authors.lastname: Hinnebusch
authors.forename: Vytas A
authors.initials: VA
authors.lastname: Bankaitis
mesh_terms: D001343:Autophagy; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D050356:Lipid Metabolism; D009584:Nitrogen / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015398:Signal Transduction; D013261:Sterols / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C501391:GCN4 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D013261:Sterols; C561842:TORC1 protein complex, S cerevisiae; D014157:Transcription Factors; D009584:Nitrogen