Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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The yeast ER-intramembrane protease Ypf1 refines nutrient sensing by regulating transporter abundance

Mol Cell. 2014 Dec 4;56(5):630-40.

Authors/Editors: Dönem Avci
Shai Fuchs
Bianca Schrul
Michal Breker
Idan Frumkin
Chia-yi Chen
Martin L. Biniossek
Elisabeth Kremmer
Oliver Schilling
Harald Steiner
Maya Schuldiner
Marius K. Lemberg
Type of Publication: Journal Article

Proteolysis by aspartyl intramembrane proteases such as presenilin and signal peptide peptidase (SPP) underlies many cellular processes in health and disease. Saccharomyces cerevisiae encodes a homolog that we named yeast presenilin fold 1 (Ypf1), which we verify to be an SPP-type protease that localizes to the endoplasmic reticulum (ER). Our work shows that Ypf1 functionally interacts with the ER-associated degradation (ERAD) factors Dfm1 and Doa10 to regulate the abundance of nutrient transporters by degradation. We demonstrate how this noncanonical branch of the ERAD pathway, which we termed "ERAD regulatory" (ERAD-R), responds to ligand-mediated sensing as a trigger. More generally, we show that Ypf1-mediated posttranslational regulation of plasma membrane transporters is indispensible for early sensing and adaptation to nutrient depletion. The combination of systematic analysis alongside mechanistic details uncovers a broad role of intramembrane proteolysis in regulating secretome dynamics.

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