Distinct targeting pathways for the membrane insertion of tail-anchored (TA) proteins

Favaloro, Vincenzo; Spasić, Milan; Schwappach, Blanche; Dobberstein, Bernhard

doi:10.1242/jcs.020321

Cited by 127 publications

(233 citation statements)

References 41 publications

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“…2A). In contrast, the addition of purified TRC40, the main endoplasmic reticulum delivery factor for Sec61β (9,18,19), had a minimal effect on Sec61β ubiquitination and the level of unmodified substrate (Fig. 2B).…”

Section: Resultsmentioning

confidence: 96%

SGTA antagonizes BAG6-mediated protein triage

Leznicki

High

2012

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

159

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The BAG6 complex was first identified as an upstream loading factor for tail-anchored membrane proteins entering the TRC40-dependent pathway for posttranslational delivery to the endoplasmic reticulum. Subsequently, BAG6 was shown to enhance the proteasomal degradation of mislocalized proteins by selectively promoting their ubiquitination. We now show that the BAG6-dependent ubiquitination of mislocalized proteins is completely reversible and identify a pivotal role for the small glutamine-rich tetratricopeptide repeatcontaining protein α (SGTA) in specifically antagonizing this process. SGTA does not simply mask the exposed hydrophobic transmembrane domain of a mislocalized protein, thereby preventing BAG6 recruitment. Rather, SGTA actively promotes the deubiquitination of mislocalized proteins that are already covalently modified, thus reversing the actions of BAG6 and inhibiting its capacity to promote substrate-specific degradation. This SGTA-mediated effect is independent of its tetratricopeptide motifs, suggesting it does not require the actions of Hsp70 and Hsp90 chaperones. These data reveal that, in a cellular context, mislocalized protein ubiquitination is the result of a dynamic equilibrium reflecting competition between pathways that promote either protein maturation or degradation. The targeted perturbation of this equilibrium, achieved by increasing steady-state SGTA levels, results in a specific stabilization of a model mislocalized protein derived from the amyloid precursor protein, an effect that is completely negated by ensuring efficient precursor delivery to the endoplasmic reticulum. We speculate that a BAG6/ SGTA cycle operates during protein maturation and quality control in the cytosol and that together these components dictate the fate of a specific subset of newly synthesized proteins. membrane protein targeting | protein homeostasis

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Section: Resultsmentioning

confidence: 96%

SGTA antagonizes BAG6-mediated protein triage

Leznicki

High

2012

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

159

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“…A different mechanism for dual localization of PDI2 invokes the nascent polypeptide-associated complex (NAC) (Powers and Walter, 1996), which modulates interactions that occur between the ribosome-nascent polypeptide chain complex, the signal recognition particle (SRP) and the ER membrane (Favaloro et al, 2008;Jackson and Blobel 1977). Accordingly, NAC would compete with SRP for the nascent PDI2.…”

Section: Discussionmentioning

confidence: 99%

Protein Disulfide Isomerase-2 of Arabidopsis Mediates Protein Folding and Localizes to Both the Secretory Pathway and Nucleus, Where It Interacts with Maternal Effect Embryo Arrest Factor

Cho

Yuen

Kang

et al. 2011

Molecules and Cells

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Protein disulfide isomerase (PDI) is a thiodisulfide oxidoreductase that catalyzes the formation, reduction and rearrangement of disulfide bonds in proteins of eukaryotes. The classical PDI has a signal peptide, two CXXCcontaining thioredoxin catalytic sites (a,a′), two noncatalytic thioredoxin fold domains (b,b′), an acidic domain (c) and a C-terminal endoplasmic reticulum (ER) retention signal. Although PDI resides in the ER where it mediates the folding of nascent polypeptides of the secretory pathway, we recently showed that PDI5 of Arabidopsis thaliana chaperones and inhibits cysteine proteases during trafficking to vacuoles prior to programmed cell death of the endothelium in developing seeds. Here we describe Arabidopsis PDI2, which shares a primary structure similar to that of classical PDI. Recombinant PDI2 is imported into ER-derived microsomes and complements the E. coli protein-folding mutant, dsbA. PDI2 interacted with proteins in both the ER and nucleus, including ER-resident protein folding chaperone, BiP1, and nuclear embryo transcription factor, MEE8. The PDI2-MEE8 interaction was confirmed to occur in vitro and in vivo. Transient expression of PDI2-GFP fusions in mesophyll protoplasts resulted in labeling of the ER, nucleus and vacuole. PDI2 is expressed in multiple tissues, with relatively high expression in seeds and root tips. Immunoelectron microscopy with GFP-and PDI2-specific antisera on transgenic seeds (PDI2-GFP) and wild type roots demonstrated that PDI2 was found in the secretory pathway (ER, Golgi, vacuole, cell wall) and the nuclei. Our results indicate that PDI2 mediates protein folding in the ER and has new functional roles in the nucleus.

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“…Large-scale genetic interaction analyses in yeast identified a clustered set of nonessential genes that produced Golgi-to-ER trafficking deficiencies that were named GET genes (Schuldiner et al 2005). Get3 shares high sequence identity with the transmembrane domain recognition complex of 40 kDa (TRC40) that had been identified through biochemical strategies in mammalian cell-free assays as a major interaction partner for newly synthesized tail-anchored proteins (Stefanovic and Hegde 2007;Favaloro et al 2008). Subsequent synthetic genetic array analyses and biochemical approaches in yeast (Jonikas et al 2009;Battle et al 2010;Chang et al 2010;Chartron et al 2010;Costanzo et al 2010) have implicated five Get proteins (Get1-5) and Sgt2 in this process.…”

Section: Polypeptide Targeting and Translocationmentioning

confidence: 99%

Secretory Protein Biogenesis and Traffic in the Early Secretory Pathway

2013

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The secretory pathway is responsible for the synthesis, folding, and delivery of a diverse array of cellular proteins. Secretory protein synthesis begins in the endoplasmic reticulum (ER), which is charged with the tasks of correctly integrating nascent proteins and ensuring correct post-translational modification and folding. Once ready for forward traffic, proteins are captured into ER-derived transport vesicles that form through the action of the COPII coat. COPII-coated vesicles are delivered to the early Golgi via distinct tethering and fusion machineries. Escaped ER residents and other cycling transport machinery components are returned to the ER via COPI-coated vesicles, which undergo similar tethering and fusion reactions. Ultimately, organelle structure, function, and cell homeostasis are maintained by modulating protein and lipid flux through the early secretory pathway. In the last decade, structural and mechanistic studies have added greatly to the strong foundation of yeast genetics on which this field was built. Here we discuss the key players that mediate secretory protein biogenesis and trafficking, highlighting recent advances that have deepened our understanding of the complexity of this conserved and essential process. TABLE OF CONTENTS Abstract 383Introduction 384

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Distinct targeting pathways for the membrane insertion of tail-anchored (TA) proteins

Cited by 127 publications

References 41 publications

SGTA antagonizes BAG6-mediated protein triage

SGTA antagonizes BAG6-mediated protein triage

Protein Disulfide Isomerase-2 of Arabidopsis Mediates Protein Folding and Localizes to Both the Secretory Pathway and Nucleus, Where It Interacts with Maternal Effect Embryo Arrest Factor

Secretory Protein Biogenesis and Traffic in the Early Secretory Pathway

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