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Function and molecular mechanism of signal peptide peptidase (SPP) in regulated membrane protein abundance control

Subject Area Biochemistry
Cell Biology
Term from 2018 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 407070872
 
Final Report Year 2023

Final Report Abstract

Intramembrane proteases are the unusual enzymes that catalyze the cleavage of peptide bonds in the hydrophobic membrane environment. Intramembrane proteolysis commonly results in the controlled protein release from the membrane and subsequent relocation to nucleus, cytosol, or extracellular space. In addition to triggering protein relocation and activation, intramembrane cleavage can also initiate regulated protein degradation. Cleavage by intramembrane proteolysis regulates important processes such as signaling, transcriptional control, and protein abundance control of proteins with key functions in metabolic pathways. Therefore, deregulation of intramembrane proteases can lead to severe pathologies such as Alzheimer's disease, tumor progression and metabolic disorders. Cellular levels of key metabolites including lipids and sterols need to be tightly regulated in order to match the changing cellular demand. For example, cholesterol levels are modulated by uptake, endogenous synthesis, intracellular storage as cholesteryl ester, and efflux to apolipoproteins, which altogether maintain membrane cholesterol homeostasis. Cholesterol is synthesized in the Endoplasmic Reticulum (ER) by the mevalonate pathway in a multistep process. An intermediate of cholesterol biosynthesis, farnesyl pyrophosphate, serves also as the building block of several other molecules including dolichol, ubiquinone, and heme. Since these isoprenoids affect important biological activities, commitment to the sterol and non-sterol branches of the mevalonate pathway needs to be tightly controlled. On one side, enzymes of the mevalonate pathway are transcriptionally upregulated by the sterol regulatory element binding protein (SREBP) in response to low cholesterol, via a process that involves intramembrane proteolysis. On the other hand, rate-limiting mevalonate pathway enzymes are under posttranslational feedback inhibition. When there is no demand for synthesis, these enzymes are targeted for turnover by the ER-associated degradation (ERAD pathway). Whereas these mechanisms determine the overall biosynthesis rate, it is unclear how shunting into sub-branches such as the sterol and non-sterol arms of the mevalonate pathway is controlled. Sensing of cholesterol levels by a number of ER membrane proteins via a conserved sterolsensing domain defines the homeostatic response to fluctuating conditions. At low cholesterol level, e.g., SREBP relocates from the ER to the Golgi, where its transcription factor domain is released and activated by regulated intramembrane proteolysis. At high cholesterol level, the HMG-CoA reductase is downregulated by ERAD. In addition to canonical ERAD dislocation mechanisms, the aspartic intramembrane protease SPP (signal peptide peptidase) forms a non-canonical ERAD mechanism. Besides its role in processing signal peptides, SPP functionally interacts with the ERAD E3 ubiquitin ligases TRC8 and MARCH6. Our recent work showed that SPP-TRC8 mediated abundance control of squalene synthase (SQS), an enzyme that defines the branching point for allocation of isoprenoids to the sterol and non-sterol arms of the mevalonate pathway, acts as a metabolic regulation mechanism. Cleavage and subsequent degradation of SQS is regulated by cholesterol and occurs through a unique module of ERAD, centered on SPP and TRC8. Consistent with this, total cellular cholesterol level is increased in SPP knockout cells, indicating that the SPP-mediated SQS abundance control mechanism is of physiological importance.

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