Transport-dependent proteolysis of SREBP: Relocation of Site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi

Department of Molecular Genetics, University of Texas, Southwestern Medical Center, Dallas 75390-9046, USA.
Cell (Impact Factor: 32.24). 12/1999; 99(7):703-12.
Source: PubMed


Cholesterol homeostasis in animal cells is achieved by regulated cleavage of membrane-bound transcription factors, designated SREBPs. Proteolytic release of the active domains of SREBPs from membranes requires a sterol-sensing protein, SCAP, which forms a complex with SREBPs. In sterol-depleted cells, SCAP escorts SREBPs from ER to Golgi, where SREBPs are cleaved by Site-1 protease (S1P). Sterols block this transport and abolish cleavage. Relocating active S1P from Golgi to ER by treating cells with brefeldin A or by fusing the ER retention signal KDEL to S1P obviates the SCAP requirement and renders cleavage insensitive to sterols. Transport-dependent proteolysis may be a common mechanism to regulate the processing of membrane proteins.

Download full-text


Available from: Axel Nohturfft, Mar 05, 2014
  • Source
    • "These findings led to speculation that lowering the PC/PE ratio in ER membranes activates ARF-GAP by altering membrane curvature, resulting in inhibition of anterograde transport and constitutive processing of SREBP-1 in the ER. In support of this theory, the ARF-GEF inhibitor brefeldin A causes transportindependent processing of SREBP-2 by relocalizing Site-1 proteases from the Golgi to the ER[112]. While ER retention of Site-1 and Site-2 proteases explains the role of PC metabolism in SREBP-1c processing, it is unclear why SREBP-2 processing was not similarly effected by changes in PC synthesis. "

    Full-text · Chapter · Jan 2016
  • Source
    • "However the requirement for S1P is absolute for the SREBPs. SRD-12B (S1P−/−) cells, which only partially prevent ATF6 processing, are able to impose a complete block of SREBPs processing [45], [50]. This would explain the specific down-regulation of SREBP-driven pathways in S1Pcko chondrocytes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The proprotein convertase site-1 protease (S1P) converts latent ER-membrane bound transcription factors SREBPs and ATF6 to their active forms. SREBPs are involved in cholesterol and fatty acid homeostasis whereas ATF6 is involved in unfolded protein response pathways (UPR). Cartilage-specific ablation of S1P in mice (S1Pcko) results in abnormal cartilage devoid of type II collagen protein (Col II). S1Pcko mice also lack endochondral bone development. To analyze S1Pcko cartilage we performed double-labeled immunofluorescence studies for matrix proteins that demonstrated that type IIB procollagen is trapped inside the ER in S1Pcko chondrocytes. This retention is specific to type IIB procollagen; other cartilage proteins such as type IIA procollagen, cartilage oligomeric matrix protein (COMP) and aggrecan are not affected. The S1Pcko cartilage thus exhibits COMP-, aggrecan-, and type IIA procollagen-derived matrices but is characterized by the absence of a type IIB procollagen-derived matrix. To understand the molecular reason behind S1Pcko phenotypes we performed genome-wide transcriptional profiling of cartilage isolated from S1Pcko and wild type littermates. While the UPR pathways are unaffected, the SREBPs-directed cholesterol and fatty acid pathways are significantly down-regulated in S1Pcko chondrocytes, with maximal down-regulation of the stearoyl-CoA desaturase-1 (Scd1) gene. However, mouse models that lack Scd1 or exhibit reduction in lipid homeostasis do not suffer from the ER retention of Col II or lack endochondral bone. These studies indicate an indispensable role for S1P in type IIB procollagen trafficking from the ER. This role appears not to be related to lipid pathways or other current known functions of S1P and is likely dependent on additional, yet unknown, S1P substrates in chondrocytes.
    Full-text · Article · Aug 2014 · PLoS ONE
  • Source
    • "In these studies, cells were treated with brefeldin A (BFA), which disrupts Golgi function by inhibiting ARF-GTPase cycles essential for protein sorting in COPI-dependent Golgi-to-ER retrograde transport (Mansour et al., 1999; Peyroche et al., 1999). When cells are treated with BFA, S1 and S2 proteases collect in the ER (Bartz et al., 2008; DeBose-Boyd et al., 1999), activating SREBP-2. We have found that availability of methyl donors or PC also alters localization of S1P and S2P (Figure 6B,C, S5B,C) and increases in mature, nuclear SREBP-1 (Figure 4C,E, S4B,C). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sterol regulatory element-binding proteins (SREBPs) activate genes involved in the synthesis and trafficking of cholesterol and other lipids and are critical for maintaining lipid homeostasis. Aberrant SREBP activity, however, can contribute to obesity, fatty liver disease, and insulin resistance, hallmarks of metabolic syndrome. Our studies identify a conserved regulatory circuit in which SREBP-1 controls genes in the one-carbon cycle, which produces the methyl donor S-adenosylmethionine (SAMe). Methylation is critical for the synthesis of phosphatidylcholine (PC), a major membrane component, and we find that blocking SAMe or PC synthesis in C. elegans, mouse liver, and human cells causes elevated SREBP-1-dependent transcription and lipid droplet accumulation. Distinct from negative regulation of SREBP-2 by cholesterol, our data suggest a feedback mechanism whereby maturation of nuclear, transcriptionally active SREBP-1 is controlled by levels of PC. Thus, nutritional or genetic conditions limiting SAMe or PC production may activate SREBP-1, contributing to human metabolic disorders.
    Full-text · Article · Nov 2011 · Cell
Show more