title: COPI-mediated retrieval of SCAP is crucial for regulating lipogenesis under basal and sterol-deficient conditions.
abstract: Retrograde trafficking from the Golgi complex to endoplasmic reticulum (ER) through COPI-coated vesicles has been implicated in lipid homeostasis. Here, we find that a block in COPI-dependent retrograde trafficking promotes processing and nuclear translocation of sterol regulatory element binding proteins (SREBPs), and upregulates the expression of downstream genes that are involved in lipid biosynthesis. This elevation in SREBP processing and activation is not caused by mislocalization of S1P or S2P (also known as MBTPS1 and MBTPS2, respectively), two Golgi-resident endoproteases that are involved in SREBP processing, but instead by increased Golgi residence of SREBPs, leading to their increased susceptibility to processing by the endoproteases. Analyses using a processing-defective SREBP mutant suggest that a fraction of SREBP molecules undergo basal cycling between the ER and Golgi in complex with SREBP cleavage-activating protein (SCAP). Furthermore, we show that SCAP alone is retrieved from the Golgi and moves to the ER after processing of SREBP under sterol-deficient conditions. Thus, our observations indicate that COPI-mediated retrograde trafficking is crucial for preventing unnecessary SREBP activation, by retrieving the small amounts of SCAP-SREBP complex that escape from the sterol-regulated ER retention machinery, as well as for the reuse of SCAP.
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Takashima
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Akina
authors.initials: A
authors.lastname: Saitoh
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Teruki
authors.initials: T
authors.lastname: Funabashi
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Hirose
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Yagi
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Nozaki
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Sato
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan Career-Path Promotion Unit for Young Life Scientists, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Hye-Won
authors.initials: HW
authors.lastname: Shin
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan kazunaka@pharm.kyoto-u.ac.jp.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nakayama
mesh_terms: D022181:COP-Coated Vesicles / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D006056:Golgi Apparatus / Q000201:enzymology / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D050155:Lipogenesis / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D008666:Metalloendopeptidases; D043484:Proprotein Convertases; D021381:Protein Transport / Q000502:physiology; D012697:Serine Endopeptidases; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C102196:SREBP cleavage-activating protein; D051779:Sterol Regulatory Element Binding Proteins; D013261:Sterols; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1; D008666:Metalloendopeptidases; C120654:MBTPS2 protein, human
keywords: COPI-coated vesicles; Golgi complex; Lipogenesis; SCAP; SREBP