Mice lacking WRB reveal differential biogenesis requirements of tail-anchored proteins in vivo
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Mice lacking WRB reveal differential biogenesis requirements of tail-anchored proteins in vivo. / Rivera-Monroy, Jhon; Musiol, Lena; Unthan-Fechner, Kirsten; Farkas, Ákos; Clancy, Anne; Coy-Vergara, Javier; Weill, Uri; Gockel, Sarah; Lin, Shuh-Yow; Corey, David P; Kohl, Tobias; Ströbel, Philipp; Schuldiner, Maya; Schwappach, Blanche; Vilardi, Fabio.
in: SCI REP-UK, Jahrgang 6, 21.12.2016, S. 39464.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Mice lacking WRB reveal differential biogenesis requirements of tail-anchored proteins in vivo
AU - Rivera-Monroy, Jhon
AU - Musiol, Lena
AU - Unthan-Fechner, Kirsten
AU - Farkas, Ákos
AU - Clancy, Anne
AU - Coy-Vergara, Javier
AU - Weill, Uri
AU - Gockel, Sarah
AU - Lin, Shuh-Yow
AU - Corey, David P
AU - Kohl, Tobias
AU - Ströbel, Philipp
AU - Schuldiner, Maya
AU - Schwappach, Blanche
AU - Vilardi, Fabio
PY - 2016/12/21
Y1 - 2016/12/21
N2 - 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.
AB - 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.
KW - Adaptor Proteins, Signal Transducing/genetics
KW - Adenosine Triphosphatases/metabolism
KW - Alleles
KW - Animals
KW - Autophagy
KW - Cytoplasm/metabolism
KW - HeLa Cells
KW - Humans
KW - Membrane Proteins/genetics
KW - Mice
KW - Mice, Knockout
KW - Myocytes, Cardiac/cytology
KW - Proteasome Endopeptidase Complex/metabolism
KW - Protein Domains
KW - Proteostasis
KW - Qa-SNARE Proteins/metabolism
KW - RNA, Small Interfering/metabolism
U2 - 10.1038/srep39464
DO - 10.1038/srep39464
M3 - SCORING: Journal article
C2 - 28000760
VL - 6
SP - 39464
JO - SCI REP-UK
JF - SCI REP-UK
SN - 2045-2322
ER -