title: Yeast SREBP cleavage activation requires the Golgi Dsc E3 ligase complex.
abstract: Mammalian lipid homeostasis requires proteolytic activation of membrane-bound sterol regulatory element binding protein (SREBP) transcription factors through sequential action of the Golgi Site-1 and Site-2 proteases. Here we report that while SREBP function is conserved in fungi, fission yeast employs a different mechanism for SREBP cleavage. Using genetics and biochemistry, we identified four genes defective for SREBP cleavage, dsc1-4, encoding components of a transmembrane Golgi E3 ligase complex with structural homology to the Hrd1 E3 ligase complex involved in endoplasmic reticulum-associated degradation. The Dsc complex binds SREBP and cleavage requires components of the ubiquitin-proteasome pathway: the E2-conjugating enzyme Ubc4, the Dsc1 RING E3 ligase, and the proteasome. dsc mutants display conserved aggravating genetic interactions with components of the multivesicular body pathway in fission yeast and budding yeast, which lacks SREBP. Together, these data suggest that the Golgi Dsc E3 ligase complex functions in a post-ER pathway for protein degradation.
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Emerson V
authors.initials: EV
authors.lastname: Stewart
authors.forename: Christine C
authors.initials: CC
authors.lastname: Nwosu
authors.forename: Zongtian
authors.initials: Z
authors.lastname: Tong
authors.forename: Assen
authors.initials: A
authors.lastname: Roguev
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Cummins
authors.forename: Dong-Uk
authors.initials: DU
authors.lastname: Kim
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Hayles
authors.forename: Han-Oh
authors.initials: HO
authors.lastname: Park
authors.forename: Kwang-Lae
authors.initials: KL
authors.lastname: Hoe
authors.forename: David W
authors.initials: DW
authors.lastname: Powell
authors.forename: Nevan J
authors.initials: NJ
authors.lastname: Krogan
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Espenshade
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism; D006056:Golgi Apparatus / Q000201:enzymology*; D046912:Multiprotein Complexes; D043484:Proprotein Convertases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012568:Schizosaccharomyces / Q000201:enzymology* / Q000235:genetics; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C489911:DSC1 protein, S pombe; D046912:Multiprotein Complexes; D029702:Schizosaccharomyces pombe Proteins; C500467:Sre1 protein, S pombe; D051779:Sterol Regulatory Element Binding Proteins; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D010450:Endopeptidases; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1; D046988:Proteasome Endopeptidase Complex; C112686:SREBP site 2 protease