title: Mice lacking WRB reveal differential biogenesis requirements of tail-anchored proteins in vivo.
abstract: Tail-anchored (TA) proteins are post-translationally inserted into membranes. The TRC40 pathway targets TA proteins to the endoplasmic reticulum via a receptor comprised of WRB and CAML. TRC40 pathway clients have been identified using in vitro assays, however, the relevance of the TRC40 pathway in vivo remains unknown. We followed the fate of TA proteins in two tissue-specific WRB knockout mouse models and found that their dependence on the TRC40 pathway in vitro did not predict their reaction to receptor depletion in vivo. The SNARE syntaxin 5 (Stx5) was extremely sensitive to disruption of the TRC40 pathway. Screening yeast TA proteins with mammalian homologues, we show that the particular sensitivity of Stx5 is conserved, possibly due to aggregation propensity of its cytoplasmic domain. We establish that Stx5 is an autophagy target that is inefficiently membrane-targeted by alternative pathways. Our results highlight an intimate relationship between the TRC40 pathway and cellular proteostasis.
authors.affiliation: Department of Molecular Biology, Universitätsmedizin Göttingen, D-37073 Göttingen, Germany.
authors.forename: Jhon
authors.initials: J
authors.lastname: Rivera-Monroy
authors.affiliation: Department of Molecular Biology, Universitätsmedizin Göttingen, D-37073 Göttingen, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Musiol
authors.affiliation: Department of Molecular Biology, Universitätsmedizin Göttingen, D-37073 Göttingen, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Unthan-Fechner
authors.affiliation: Department of Molecular Biology, Universitätsmedizin Göttingen, D-37073 Göttingen, Germany.
authors.forename: Ákos
authors.initials: Á
authors.lastname: Farkas
authors.affiliation: Department of Molecular Biology, Universitätsmedizin Göttingen, D-37073 Göttingen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Clancy
authors.affiliation: Department of Molecular Biology, Universitätsmedizin Göttingen, D-37073 Göttingen, Germany.
authors.forename: Javier
authors.initials: J
authors.lastname: Coy-Vergara
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Uri
authors.initials: U
authors.lastname: Weill
authors.affiliation: Department of Cardiology &Pulmonology, Universitätsmedizin Göttingen, D-37075 Göttingen, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gockel
authors.affiliation: Howard Hughes Medical Institute and Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
authors.forename: Shuh-Yow
authors.initials: SY
authors.lastname: Lin
authors.affiliation: Howard Hughes Medical Institute and Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Corey
authors.affiliation: Department of Cardiology &Pulmonology, Universitätsmedizin Göttingen, D-37075 Göttingen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Kohl
authors.affiliation: Institute of Pathology, Universitätsmedizin Göttingen, D-37073 Göttingen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Ströbel
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Schuldiner
authors.affiliation: Department of Molecular Biology, Universitätsmedizin Göttingen, D-37073 Göttingen, Germany.|Max-Planck Institute for Biophysical Chemistry, D-37077, Göttingen, Germany.
authors.forename: Blanche
authors.initials: B
authors.lastname: Schwappach
authors.affiliation: Department of Molecular Biology, Universitätsmedizin Göttingen, D-37073 Göttingen, Germany.
authors.forename: Fabio
authors.initials: F
authors.lastname: Vilardi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D001343:Autophagy; D003593:Cytoplasm / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D000072417:Protein Domains; D000074702:Proteostasis; D050765:Qa-SNARE Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490314:Caml protein, mouse; D008565:Membrane Proteins; D050765:Qa-SNARE Proteins; D034741:RNA, Small Interfering; C000627975:WRB protein, mouse; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases