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Intramembrane protease SPP defines a cholesterol-regulated switch of the mevalonate pathway

Heidasch, R.; Avci, D.; Lüchtenborg, C.; Kale, D.; Beard, H.; Mentrup, T.; Barniol-Xicota, M.; Schröder, B.; verhelst, S.; Brügger, B.; Lemberg, M. K.

2021-07-20 cell biology
10.1101/2021.07.19.452877 bioRxiv
Show abstract

Intramembrane proteolysis regulates important processes such as signaling and transcriptional and posttranslational abundance control of proteins with key functions in metabolic pathways. This includes transcriptional control of mevalonate pathway genes, thereby ensuring balanced biosynthesis of cholesterol and other isoprenoids. Our work shows that, at high cholesterol levels, signal peptide peptidase (SPP) cleaves 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. This intramembrane cleavage releases SQS from the membrane and targets it for proteasomal degradation. Regulation of this mechanism is achieved by the E3 ubiquitin ligase TRC8 that, in addition to ubiquitinating SQS in response to cholesterol levels, acts as an allosteric activator of SPP-catalyzed intramembrane cleavage of SQS. Cellular cholesterol levels increase in the absence of SPP activity. Hence, SPP-TRC8 mediated abundance control of SQS acts as a regulation step within the mevalonate pathway.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.