The Yeast ER-Intramembrane Protease Ypf1 Refines Nutrient Sensing by Regulating Transporter Abundance

Dönem Avci, Shai Fuchs, Bianca Schrul, Akio Fukumori, Michal Breker, Idan Frumkin, Chia Yi Chen, Martin L. Biniossek, Elisabeth Kremmer, Oliver Schilling, Harald Steiner, Maya Schuldiner*, Marius K. Lemberg

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


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.

Original languageAmerican English
Pages (from-to)630-640
Number of pages11
JournalMolecular Cell
Issue number5
StatePublished - 4 Dec 2014
Externally publishedYes

Bibliographical note

Funding Information:
We thank B. Dobberstein, B. Bukau, M. Seedorf, D. Eide, D. Wolf, J. Brodsky, N. Malchus, H. Lorenz, T. Uhlig, B. Mayer, D. Schlesinger, M. Kafri, M. Carmi, N. Vardi, N. Avraham-Tayar, Y. Pilpel, R. Milo, N. Barkai, G. Basset, and A. Sülzen for reagents, advice, and technical assistance. The work was supported by funds from the Baden-Württemberg Stiftung within the Network of Aging Research (NAR, University of Heidelberg) and the Deutsche Forschungsgemeinschaft (SFB 1036, TP 12) to M.K.L.; Estate of Sunny Howard and Michael Jacobs Charitable Trust fellowships to S.F.; an ERC StG 260395, a Marie Curie Reintegration Grant from the EU (IRG 239224), and the generous support of Ruhman Roberto and Renata to M.S. and S.F.; the Hans and Ilse Breuer Foundation to H.S.; and the Excellence Initiative of the German Federal and State Governments (EXC 294, BIOSS) to O.S.

Publisher Copyright:
© 2014 Elsevier Inc.


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