title: Yeast sterol regulatory element-binding protein (SREBP) cleavage requires Cdc48 and Dsc5, a ubiquitin regulatory X domain-containing subunit of the Golgi Dsc E3 ligase.
abstract: Schizosaccharomyces pombe Sre1 is a membrane-bound transcription factor that controls adaptation to hypoxia. Like its mammalian homolog, sterol regulatory element-binding protein (SREBP), Sre1 activation requires release from the membrane. However, in fission yeast, this release occurs through a strikingly different mechanism that requires the Golgi Dsc E3 ubiquitin ligase complex and the proteasome. The mechanistic details of Sre1 cleavage, including the link between the Dsc E3 ligase complex and proteasome, are not well understood. Here, we present results of a genetic selection designed to identify additional components required for Sre1 cleavage. From the selection, we identified two new components of the fission yeast SREBP pathway: Dsc5 and Cdc48. The AAA (ATPase associated with diverse cellular activities) ATPase Cdc48 and Dsc5, a ubiquitin regulatory X domain-containing protein, interact with known Dsc complex components and are required for SREBP cleavage. These findings provide a mechanistic link between the Dsc E3 ligase complex and the proteasome in SREBP cleavage and add to a growing list of similarities between the Dsc E3 ligase and membrane E3 ligases involved in endoplasmic reticulum-associated degradation.
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Emerson V
authors.initials: EV
authors.lastname: Stewart
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: S Julie-Ann
authors.initials: SJ
authors.lastname: Lloyd
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: John S
authors.initials: JS
authors.lastname: Burg
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Christine C
authors.initials: CC
authors.lastname: Nwosu
authors.affiliation: Genome Sequencing and Analysis Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02141.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Lintner
authors.affiliation: Genome Sequencing and Analysis Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02141.
authors.forename: Riza
authors.initials: R
authors.lastname: Daza
authors.affiliation: Genome Sequencing and Analysis Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02141.
authors.forename: Carsten
authors.initials: C
authors.lastname: Russ
authors.affiliation: Genome Sequencing and Analysis Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02141.
authors.forename: Karen
authors.initials: K
authors.lastname: Ponchner
authors.affiliation: Genome Sequencing and Analysis Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02141.
authors.forename: Chad
authors.initials: C
authors.lastname: Nusbaum
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. Electronic address: peter.espenshade@jhmi.edu.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Espenshade
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D016296:Mutagenesis; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism*; D059748:Proteolysis; D012568:Schizosaccharomyces / Q000166:cytology / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry / Q000378:metabolism*; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry*; D000074405:Valosin Containing Protein
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C571906:Dsc5 protein, S pombe; D008565:Membrane Proteins; D021122:Protein Subunits; D029702:Schizosaccharomyces pombe Proteins; C500467:Sre1 protein, S pombe; D051779:Sterol Regulatory Element Binding Proteins; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein
references.citation: Anal Biochem. 1991 Feb 1;192(2):262-7
references.pmid: 1852137
references.citation: Methods Enzymol. 1987;154:164-75
references.pmid: 3323810
references.citation: Mol Cell. 2011 Apr 22;42(2):160-71
references.pmid: 21504829
references.citation: Genes Cells. 2004 Nov;9(11):1069-82
references.pmid: 15507118
references.citation: J Struct Biol. 2004 Apr-May;146(1-2):44-57
references.pmid: 15037236
references.citation: Cell. 2006 Jan 13;124(1):35-46
references.pmid: 16413480
references.citation: Curr Biol. 2004 May 4;14(9):824-8
references.pmid: 15120077
references.citation: Cell Mol Life Sci. 2008 Aug;65(15):2360-71
references.pmid: 18438607
references.citation: J Lipid Res. 2008 Sep;49(9):2001-12
references.pmid: 18503029
references.citation: Eukaryot Cell. 2005 Apr;4(4):799-813
references.pmid: 15821139
references.citation: EMBO J. 2009 Jan 21;28(2):135-43
references.pmid: 19158663
references.citation: Int J Biochem Cell Biol. 2003 May;35(5):629-36
references.pmid: 12672455
references.citation: Cell. 2008 Sep 5;134(5):804-16
references.pmid: 18775313
references.citation: Eukaryot Cell. 2010 Mar;9(3):352-9
references.pmid: 20118213
references.citation: Mol Cell Biol. 2006 Apr;26(7):2817-31
references.pmid: 16537923
references.citation: Mol Gen Genet. 1994 Jan;242(2):169-76
references.pmid: 8159167
references.citation: Yeast. 1998 Jul;14(10):943-51
references.pmid: 9717240
references.citation: Nat Cell Biol. 2002 Feb;4(2):117-23
references.pmid: 11788821
references.citation: Cell. 2006 Jul 28;126(2):361-73
references.pmid: 16873066
references.citation: Nat Cell Biol. 2005 Oct;7(10):999-1006
references.pmid: 16179952
references.citation: Nucleic Acids Res. 1993 Jun 25;21(12):2955-6
references.pmid: 8332516
references.citation: Mol Cell. 2006 May 19;22(4):451-62
references.pmid: 16713576
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D225-9
references.pmid: 21109532
references.citation: Cell. 2000 Aug 4;102(3):315-23
references.pmid: 10975522
references.citation: Nat Cell Biol. 2005 Oct;7(10):993-8
references.pmid: 16179953
references.citation: J Biol Chem. 2005 Dec 9;280(49):40515-23
references.pmid: 16216872
references.citation: Nature. 2002 Feb 21;415(6874):871-80
references.pmid: 11859360
references.citation: Trends Biochem Sci. 2011 Oct;36(10):515-23
references.pmid: 21741246
references.citation: EMBO J. 2006 May 3;25(9):1827-35
references.pmid: 16619026
references.citation: Mol Microbiol. 2007 Aug;65(4):1018-33
references.pmid: 17645443
references.citation: Cell. 2006 Jul 28;126(2):349-59
references.pmid: 16873065
references.citation: Ann Med. 2004;36(4):315-20
references.pmid: 15224658
references.citation: Annu Rev Genet. 2007;41:401-27
references.pmid: 17666007
references.citation: Mol Cell Biol. 2009 Aug;29(16):4484-94
references.pmid: 19506019
references.citation: Nat Biotechnol. 2010 Jun;28(6):617-623
references.pmid: 20473289
references.citation: Cell. 2005 Mar 25;120(6):831-42
references.pmid: 15797383
references.citation: Genes Dev. 2009 Nov 15;23(22):2578-91
references.pmid: 19933148