title: The yeast ER-intramembrane protease Ypf1 refines nutrient sensing by regulating transporter abundance.
abstract: 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.
authors.affiliation: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Allianz, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
authors.forename: Dönem
authors.initials: D
authors.lastname: Avci
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Shai
authors.initials: S
authors.lastname: Fuchs
authors.affiliation: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Allianz, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Schrul
authors.affiliation: Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität, 86336 Munich, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 86336 Munich, Germany.
authors.forename: Akio
authors.initials: A
authors.lastname: Fukumori
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Breker
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Idan
authors.initials: I
authors.lastname: Frumkin
authors.affiliation: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Allianz, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Institut für Molekulare Medizin und Zellforschung and BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-Universität, 79104 Freiburg, Germany.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Biniossek
authors.affiliation: Institute of Molecular Immunology, Helmholtz Center Munich, 81377 Munich, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.affiliation: Institut für Molekulare Medizin und Zellforschung and BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-Universität, 79104 Freiburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Schilling
authors.affiliation: Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität, 86336 Munich, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 86336 Munich, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Steiner
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address: maya.schuldiner@weizmann.ac.il.
authors.forename: Maya
authors.initials: M
authors.lastname: Schuldiner
authors.affiliation: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Allianz, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany. Electronic address: m.lemberg@zmbh.uni-heidelberg.de.
authors.forename: Marius K
authors.initials: MK
authors.lastname: Lemberg
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation; D015966:Gene Expression Regulation, Fungal; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D010447:Peptide Hydrolases / Q000235:genetics* / Q000378:metabolism*; D010802:Phylogeny; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism*; D016415:Sequence Alignment; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
chemical_list: C530209:Dfm1 protein, S cerevisiae; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D029701:Saccharomyces cerevisiae Proteins; C091362:SSM4 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; C000594976:Ypf1 protein, S cerevisiae; D015032:Zinc