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, Sunny Jui-Shan; Corey, David P.; Kohl, Tobias; Ströbel, Philipp; Schuldiner, Maya; Schwappach, Blanche; Vilardi, Fabio

doi:10.1038/srep39464

Cited by 37 publications

(78 citation statements)

References 62 publications

(111 reference statements)

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“…Also, cytosolic chaperone calmodulin was shown to promote posttranslational membrane targeting of small secretory proteins while inhibiting the insertion of various TA . Studies addressing biogenesis of tail‐anchored and short secretory clients in vivo using tissue‐specific WRB (hepatocytes, cardiomyocytes) or TRC40 (pancreatic β‐cells) gene knockouts demonstrated heterogeneous, cell‐type‐specific requirements for proper protein topogenesis of different such precursors . Varying targeting requirements of different TA are also reflected by our observations for the multifacetedly targeting Cytb5‐ops28 and the strictly TRC‐dependent Sec61β‐ops13 in epithelial (HeLa) cells.…”

Section: Discussionsupporting

confidence: 56%

“…Further details are given in the text. specific WRB (hepatocytes, cardiomyocytes) or TRC40 (pancreatic b-cells) gene knockouts demonstrated heterogeneous, cell-type-specific requirements for proper protein topogenesis of different such precursors [47][48][49]. Varying targeting requirements of different TA are also reflected by our observations for the multifacetedly targeting Cytb5-ops28 and the strictly TRCdependent Sec61b-ops13 in epithelial (HeLa) cells.…”

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confidence: 63%

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hSnd2 protein represents an alternative targeting factor to the endoplasmic reticulum in human cells

et al. 2017

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Recently, understanding of protein targeting to the endoplasmic reticulum (ER) was expanded by the discovery of multiple pathways that function in parallel to the signal recognition particle (SRP). Guided entry of tail-anchored proteins and SRP independent (SND) are two such targeting pathways described in yeast. So far, no human SND component is functionally characterized. Here, we report hSnd2 as the first constituent of the human SND pathway able to support substrate-specific protein targeting to the ER. Similar to its yeast counterpart, hSnd2 is assumed to function as a membrane-bound receptor preferentially targeting precursors carrying C-terminal transmembrane domains. Our genetic and physical interaction studies show that hSnd2 is part of a complex network of targeting and translocation that is dynamically regulated.

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Section: Discussionsupporting

confidence: 56%

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confidence: 63%

hSnd2 protein represents an alternative targeting factor to the endoplasmic reticulum in human cells

et al. 2017

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“…It was therefore surprising that mutants of get3 in Saccharomyces cerevisiae or Arabidopsis thaliana did not show any global growth defects [51]. Moreover, while many different TA proteins were found to employ the Get3/TRC40 system for successful membrane targeting in vitro , in vivo studies in yeast or tissue-specific knockout mice failed to identify more than a handful of proteins that show targeting defects [52]. This is likely because at least two functional backup systems exist that take over the targeting of TA proteins in the absence of the GET pathway [53, 54].…”

Section: Get3: the Link To Redox-regulated Chaperones In Eukaryotesmentioning

confidence: 99%

Stress-Activated Chaperones: A First Line of Defense

Voth

Jakob

2017

Trends in Biochemical Sciences

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Proteins are constantly challenged by environmental stress conditions that threaten their structure and function. Especially problematic are oxidative, acid, or severe heat stress, which induce very rapid and widespread protein unfolding and generate conditions that make canonical chaperones and/or transcriptional responses inadequate to protect the proteome. Here, we review recent advances in identifying and characterizing stress-activated chaperones, which are inactive under non-stress conditions but become potent chaperones under specific protein-unfolding stress conditions. We discuss the posttranslational mechanisms by which these chaperones sense stress and consider the role intrinsic disorder plays in their regulation and function. We examine their physiological roles under both non-stress and stress conditions, their integration into the cellular proteostasis network, and their potential as novel therapeutic targets.

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“…During revision of this article, an analysis of conditional wrb KO mice demonstrated that the GET pathway is required for only a subset--but not all-TA proteins in vivo (67). Also, an alternative ER insertion pathway was described in yeast (68) and another study reported an ER-stress and early flowering phenotype of the Atget1-1 and Atget3a-1 lines (69).…”

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confidence: 99%

Loss of GET pathway orthologs in Arabidopsis thaliana causes root hair growth defects and affects SNARE abundance

Xing

Mehlhorn

Wallmeroth

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

109

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Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins are key players in cellular trafficking and coordinate vital cellular processes, such as cytokinesis, pathogen defense, and ion transport regulation. With few exceptions, SNAREs are tail-anchored (TA) proteins, bearing a C-terminal hydrophobic domain that is essential for their membrane integration. Recently, the Guided Entry of Tail-anchored proteins (GET) pathway was described in mammalian and yeast cells that serve as a blueprint of TA protein insertion [Schuldiner M, et al. (2008) Cell 134(4):634-645; Stefanovic S, Hegde RS (2007) Cell 128(6):1147-1159]. This pathway consists of six proteins, with the cytosolic ATPase GET3 chaperoning the newly synthesized TA protein posttranslationally from the ribosome to the endoplasmic reticulum (ER) membrane. Structural and biochemical insights confirmed the potential of pathway components to facilitate membrane insertion, but the physiological significance in multicellular organisms remains to be resolved. Our phylogenetic analysis of 37 GET3 orthologs from 18 different species revealed the presence of two different GET3 clades. We identified and analyzed GET pathway components in Arabidopsis thaliana and found reduced root hair elongation in Atget lines, possibly as a result of reduced SNARE biogenesis. Overexpression of AtGET3a in a receptor knockout (KO) results in severe growth defects, suggesting presence of alternative insertion pathways while highlighting an intricate involvement for the GET pathway in cellular homeostasis of plants.GET pathway | TA proteins | SNAREs | ER membrane | root hairs

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Mice lacking WRB reveal differential biogenesis requirements of tail-anchored proteins in vivo

Cited by 37 publications

References 62 publications

hSnd2 protein represents an alternative targeting factor to the endoplasmic reticulum in human cells

hSnd2 protein represents an alternative targeting factor to the endoplasmic reticulum in human cells

Stress-Activated Chaperones: A First Line of Defense

Loss of GET pathway orthologs in Arabidopsis thaliana causes root hair growth defects and affects SNARE abundance

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