Regulated intramembrane proteolysis: from the endoplasmic reticulum to the nucleus

2002 ◽  
Vol 38 ◽  
pp. 155-168 ◽  
Author(s):  
Robert B Rawson
Keyword(s):  
Endoplasmic Reticulum ◽  
Regulatory Element ◽  
Transmembrane Proteins ◽  
Intramembrane Proteolysis ◽  
Regulated Intramembrane Proteolysis ◽  
Class 1 ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Membrane Spanning ◽  
Highly Hydrophobic

Regulated intramembrane proteolysis (Rip) is an ancient and widespread process by which cells transmit information from one compartment (the endoplasmic reticulum) to another (the nucleus). Two separate cleavages that are carried out by two separate proteases are required for Rip. The first protease cleaves its protein substrate within an extracytoplasmic domain; the second cleaves it within a membrane-spanning domain, releasing a functionally active fragment of the target protein. In eukaryotes, examples of Rip can be divided into two classes, according to the proteases that are involved and the orientation of the substrates with the membrane. Class 1 Rip involves type 1 transmembrane proteins and requires presenilin for cleavage within a membrane-spanning domain. In Class 2 Rip, the highly hydrophobic metalloprotease, site-2 protease, is required for cleavage within a membrane-spanning domain and substrates are type 2 transmembrane proteins. Both classes of Rip are implicated in diseases that are important in modern societies, such as hyperlipidaemias (via the sterol regulatory element binding protein pathway) and Alzheimer's disease (via processing of the amyloid precursor protein.)

SREBP-1c and lipogenesis in the liver: an update

2021 ◽  
Vol 478 (20) ◽  
pp. 3723-3739
Author(s):  
Pascal Ferré ◽  
Franck Phan ◽  
Fabienne Foufelle
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Endoplasmic Reticulum Stress ◽  
Binding Protein ◽  
Regulatory Element ◽  
Activation Process ◽  
Lipogenic Genes ◽  
Regulated Intramembrane Proteolysis ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Sterol Regulatory Element Binding Protein-1c is a transcription factor that controls the synthesis of lipids from glucose in the liver, a process which is of utmost importance for the storage of energy. Discovered in the early nineties by B. Spiegelman and by M. Brown and J. Goldstein, it has generated more than 5000 studies in order to elucidate its mechanism of activation and its role in physiology and pathology. Synthetized as a precursor found in the membranes of the endoplasmic reticulum, it has to be exported to the Golgi and cleaved by a mechanism called regulated intramembrane proteolysis. We reviewed in 2002 its main characteristics, its activation process and its role in the regulation of hepatic glycolytic and lipogenic genes. We particularly emphasized that Sterol Regulatory Element Binding Protein-1c is the mediator of insulin effects on these genes. In the present review, we would like to update these informations and focus on the response to insulin and to another actor in Sterol Regulatory Element Binding Protein-1c activation, the endoplasmic reticulum stress.

Control of lipid metabolism by regulated intramembrane proteolysis of sterol regulatory element binding proteins (SREBPs)

2003 ◽  
Vol 70 ◽  
pp. 221-231 ◽  
Author(s):  
Robert B Rawson
Keyword(s):  
Mammalian Cells ◽  
Transcriptional Control ◽  
Binding Proteins ◽  
Regulatory Element ◽  
Lipid Level ◽  
Transmembrane Helices ◽  
Intramembrane Proteolysis ◽  
Terminal Domain ◽  
Regulated Intramembrane Proteolysis ◽  
Sterol Regulatory Element

In mammalian cells, the supply of lipids is co-ordinated with demand through the transcriptional control of genes encoding proteins required for synthesis or uptake. The sterol regulatory element binding proteins (SREBPs) are responsible for increased transcription of these genes when lipid level fall. Mammals have three SREBPs (-1a, -1c and -2), which are the products of two distinct genes. Synthesized as approximately 120 kDa precursors, they are inserted into membranes of the endoplasmic reticulum (ER) in a hairpin fashion. Both the N-terminal transcription factor domain and the C-terminal regulatory domain face the cytoplasm. These are connected by two transmembrane helices separated by a short loop projecting into the ER lumen. The C-terminal domain of SREBP interacts with the C-terminal domain of SREBP-cleavage-activating protein (SCAP). The N-terminal half of SCAP contains eight transmembrane helices, five of which (helices 2-6) form the sterol-sensing domain. In response to cellular demand for lipid, this complex exits the ER and transits to the Golgi apparatus, where two distinct proteases cleave the SREBP precursor to release the transcriptionally active N-terminus. This process was the first example of regulated intramembrane proteolysis for which the proteases were identified. Recent work has additionally uncovered integral membrane proteins, insig-1 and insig-2, that are required to retain the SREBP-SCAP complex in the ER in the presence of sterols, thus providing a more complete understanding of the control of proteolysis in this complex regulatory pathway.

scholarly journals Subunit Architecture of the Golgi Dsc E3 Ligase Required for Sterol Regulatory Element-binding Protein (SREBP) Cleavage in Fission Yeast

2013 ◽  
Vol 288 (29) ◽  
pp. 21043-21054 ◽  
Author(s):  
S. Julie-Ann Lloyd ◽  
Sumana Raychaudhuri ◽  
Peter J. Espenshade
Keyword(s):  
Endoplasmic Reticulum ◽  
Fission Yeast ◽  
Binding Protein ◽  
Regulatory Element ◽  
E3 Ligase ◽  
E3 Ligases ◽  
Endoplasmic Reticulum Associated Degradation ◽  
Element Binding Protein ◽  
Uba Domain ◽  
Sterol Regulatory Element

The membrane-bound sterol regulatory element-binding protein (SREBP) transcription factors regulate lipogenesis in mammalian cells and are activated through sequential cleavage by the Golgi-localized Site-1 and Site-2 proteases. The mechanism of fission yeast SREBP cleavage is less well defined and, in contrast, requires the Golgi-localized Dsc E3 ligase complex. The Dsc E3 ligase consists of five integral membrane subunits, Dsc1 through Dsc5, and resembles membrane E3 ligases that function in endoplasmic reticulum-associated degradation. Using immunoprecipitation assays and blue native electrophoresis, we determined the subunit architecture for the complex of Dsc1 through Dsc5, showing that the Dsc proteins form subcomplexes and display defined connectivity. Dsc2 is a rhomboid pseudoprotease family member homologous to mammalian UBAC2 and a central component of the Dsc E3 ligase. We identified conservation in the architecture of the Dsc E3 ligase and the multisubunit E3 ligase gp78 in mammals. Specifically, Dsc1-Dsc2-Dsc5 forms a complex resembling gp78-UBAC2-UBXD8. Further characterization of Dsc2 revealed that its C-terminal UBA domain can bind to ubiquitin chains but that the Dsc2 UBA domain is not essential for yeast SREBP cleavage. Based on the ability of rhomboid superfamily members to bind transmembrane proteins, we speculate that Dsc2 functions in SREBP recognition and binding. Homologs of Dsc1 through Dsc4 are required for SREBP cleavage and virulence in the human opportunistic pathogen Aspergillus fumigatus. Thus, these studies advance our organizational understanding of multisubunit E3 ligases involved in endoplasmic reticulum-associated degradation and fungal pathogenesis.

scholarly journals Effectors of Rapid Homeostatic Responses of Endoplasmic Reticulum Cholesterol and 3-Hydroxy-3-methylglutaryl-CoA Reductase

2007 ◽  
Vol 283 (3) ◽  
pp. 1445-1455 ◽  
Author(s):  
Yvonne Lange ◽  
Daniel S. Ory ◽  
Jin Ye ◽  
Michael H. Lanier ◽  
Fong-Fu Hsu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endoplasmic Reticulum ◽  
Regulatory Element ◽  
Cholesterol Content ◽  
Cholesterol Levels ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Hmgr Activity ◽  
Coa Reductase ◽  
Cholesterol Precursors

The cholesterol content of the endoplasmic reticulum (ER) and the activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) imbedded therein respond homeostatically within minutes to changes in the level of plasma membrane cholesterol. We have now examined the roles of sterol regulatory element-binding protein (SREBP)-dependent gene expression, side chain oxysterol biosynthesis, and cholesterol precursors in the short term regulation of ER cholesterol levels and HMGR activity. We found that SREBP-dependent gene expression is not required for the response to changes in cell cholesterol of either the pool of ER cholesterol or the rate of cholesterol esterification. It was also found that the acute proteolytic inactivation of HMGR triggered by cholesterol loading required the conversion of cholesterol to 27-hydroxycholesterol. High levels of exogenous 24,25-dihydrolanosterol drove the inactivation of HMGR; lanosterol did not. However, purging endogenous 24,25-dihydrolanosterol, lanosterol, and other biosynthetic sterol intermediates by treating cells with NB-598 did not greatly affect either the setting of their ER cholesterol pool or the inactivation of their HMGR. In summary, neither SREBP-regulated genes nor 27-hydroxycholesterol is involved in setting the ER cholesterol pool. On the other hand, 27-hydroxycholesterol, rather than cholesterol itself or biosynthetic precursors of cholesterol, stimulates the rapid inactivation of HMGR in response to high levels of cholesterol.

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