title: Signal peptide peptidase functions in ERAD to cleave the unfolded protein response regulator XBP1u.
abstract: Signal peptide peptidase (SPP) catalyzes intramembrane proteolysis of signal peptides at the endoplasmic reticulum (ER), but has also been suggested to play a role in ER-associated degradation (ERAD). Here, we show that SPP forms a complex with the ERAD factor Derlin1 and the E3 ubiquitin ligase TRC8 to cleave the unfolded protein response (UPR) regulator XBP1u. Cleavage occurs within a so far unrecognized type II transmembrane domain, which renders XBP1u as an SPP substrate through specific sequence features. Additionally, Derlin1 acts in the complex as a substrate receptor by recognizing the luminal tail of XBP1u. Remarkably, this interaction of Derlin1 with XBP1u obviates the need for ectodomain shedding prior to SPP cleavage, commonly required for intramembrane cuts. Furthermore, we show that XBP1u inhibits the UPR transcription factor XBP1s by targeting it toward proteasomal degradation. Thus, we identify an ERAD complex that controls the abundance of XBP1u and thereby tunes signaling through the UPR.
authors.affiliation: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) DKFZ-ZMBH Allianz, Heidelberg, Germany.
authors.forename: Chia-yi
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) DKFZ-ZMBH Allianz, Heidelberg, Germany.
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Malchus
authors.affiliation: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) DKFZ-ZMBH Allianz, Heidelberg, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Hehn
authors.affiliation: Lehrstuhl für Chemie der Biopolymere, Department für Biowissenschaftliche Grundlagen, Technische Universität München, Freising, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Stelzer
authors.affiliation: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) DKFZ-ZMBH Allianz, Heidelberg, Germany.
authors.forename: Dönem
authors.initials: D
authors.lastname: Avci
authors.affiliation: Lehrstuhl für Chemie der Biopolymere, Department für Biowissenschaftliche Grundlagen, Technische Universität München, Freising, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Langosch
authors.affiliation: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH) DKFZ-ZMBH Allianz, Heidelberg, Germany m.lemberg@zmbh.uni-heidelberg.de.
authors.forename: Marius K
authors.initials: MK
authors.lastname: Lemberg
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071717:X-Box Binding Protein 1
chemical_list: C487709:DERL1 protein, human; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; C114025:RNF139 protein, human; D011956:Receptors, Cell Surface; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D012697:Serine Endopeptidases; C026515:type I signal peptidase; D046988:Proteasome Endopeptidase Complex
keywords: E3 ubiquitin‐protein ligase; GxGD intramembrane protease; protein homeostasis; rhomboid pseudoprotease