<scp>hS</scp>nd2 protein represents an alternative targeting factor to the endoplasmic reticulum in human cells

Haßdenteufel, Sarah; Sicking, Mark; Schorr, Stefan; Aviram, Naama; Fecher‐Trost, Claudia; Schuldiner, Maya; Jung, Martin; Zimmermann, Richard; Lang, Sven

doi:10.1002/1873-3468.12831

Cited by 65 publications

(150 citation statements)

References 55 publications

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“…Δsgt2 cells exhibited a more modest defect in mediating rapid Bos1 targeting and insertion into the ER (Fig EV4C and D), consistent with previous observations (Kohl et al, 2011;Kiktev et al, 2012;Yeh et al, 2014). As reported, alternative pathways could enable the targeting of TAs when Sgt2 or Get3 was deleted (Aviram et al, 2016;Haßdenteufel et al, 2017), which may account for the observed TA targeting at steady state.…”

Section: Cytosolic Hsp70 Is Important For the Biogenesis Of Get Substsupporting

confidence: 90%

Substrate relay in an Hsp70‐cochaperone cascade safeguards tail‐anchored membrane protein targeting

2018

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Membrane proteins are aggregation-prone in aqueous environments, and their biogenesis poses acute challenges to cellular protein homeostasis. How the chaperone network effectively protects integral membrane proteins during their post-translational targeting is not well understood. Here, biochemical reconstitutions showed that the yeast cytosolic Hsp70 is responsible for capturing newly synthesized tail-anchored membrane proteins (TAs) in the soluble form. Moreover, direct interaction of Hsp70 with the cochaperone Sgt2 initiates a sequential series of TA relays to the dedicated TA targeting factor Get3. In contrast to direct loading of TAs to downstream chaperones, stepwise substrate loading via Hsp70 maintains the solubility and targeting competence of TAs, ensuring their efficient delivery to the endoplasmic reticulum (ER). Inactivation of cytosolic Hsp70 severely impairs TA translocation Our results demonstrate a new role of cytosolic Hsp70 in directly assisting the targeting of an essential class of integral membrane proteins and provide a paradigm for how "substrate funneling" through a chaperone cascade preserves the conformational quality of nascent membrane proteins during their biogenesis.

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Section: Cytosolic Hsp70 Is Important For the Biogenesis Of Get Substsupporting

confidence: 90%

Substrate relay in an Hsp70‐cochaperone cascade safeguards tail‐anchored membrane protein targeting

2018

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“…Of note, we observed that ∼30-40% of b5-RR molecules are localized to ER, even in the absence of functional GET system. This partial dependence on the GET components is in line with the idea that multiple selection filters are used by the GET machinery to assure correct targeting (Rao et al, 2016), and that alternative pathways, involving SRP, hSnd2 and/or unassisted membrane integration, exist for ER TA protein targeting in the absence of GET (Casson et al, 2017;Hassdenteufel et al, 2017).…”

Section: Results and Discussion Get-dependent Mislocalization Of Cytosupporting

confidence: 67%

“…with the N-terminus in the lumen. These findings can be explained by recent reports suggesting that the SRP and the Sec translocon are involved in the targeting of some TA proteins, including cytochrome b5, to the ER (Casson et al, 2017;Hassdenteufel et al, 2017). Thus, it might be that the Sec translocon mediates an integration of a sub-population of b5-RR into the ER membrane in the wrong topology.…”

Section: Results and Discussion Get-dependent Mislocalization Of Cytomentioning

confidence: 87%

“…cytochrome b5 and the protein tyrosine phosphatase PTP1B, can spontaneously insert into the lipid bilayer (Brambillasca et al, 2005;Colombo et al, 2009). Recently, an additional ER membrane protein targeting pathway was identified, which can compensate the absence of either the signal recognition particle (SRP) or of the GET machinery and was named SRPindependent targeting (SND) pathway (Aviram et al, 2016;Hassdenteufel et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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The GET pathway can increase the risk of mitochondrial outer membrane proteins to be mistargeted to the ER

Vitali

Sinzel

Bulthuis

et al. 2018

Journal of Cell Science

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Tail-anchored (TA) proteins are anchored to their corresponding membrane via a single transmembrane segment (TMS) at their C-terminus. In yeast, the targeting of TA proteins to the endoplasmic reticulum (ER) can be mediated by the guided entry of TA proteins (GET) pathway, whereas it is not yet clear how mitochondrial TA proteins are targeted to their destination. It has been widely observed that some mitochondrial outer membrane (MOM) proteins are mistargeted to the ER when overexpressed or when their targeting signal is masked. However, the mechanism of this erroneous sorting is currently unknown. In this study, we demonstrate the involvement of the GET machinery in the mistargeting of suboptimal MOM proteins to the ER. These findings suggest that the GET machinery can, in principle, recognize and guide mitochondrial and non-canonical TA proteins. Hence, under normal conditions, an active mitochondrial targeting pathway must exist that dominates the kinetic competition against other pathways.

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“…Such a redundancy among several parallel potential pathways was demonstrated lately for the insertion pathway of ER TA proteins. The newly discovered SND pathway (hSND in humans) can complement the loss of the Get/TRC40 or SRP pathway and most probably even the disruption of both pathways together …”

Section: Discussionmentioning

confidence: 99%

Pex19 is involved in importing dually targeted tail‐anchored proteins to both mitochondria and peroxisomes

Cichocki

Krumpe

Vitali

et al. 2018

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Tail-anchored (TA) proteins are embedded into their corresponding membrane via a single transmembrane segment at their C-terminus whereas the majority of the protein is facing the cytosol. So far, cellular factors that mediate the integration of such proteins into the mitochondrial outer membrane were not found. Using budding yeast as a model system, we identified the cytosolic Hsp70 chaperone Ssa1 and the peroxisome import factor Pex19 as import mediators for a subset of mitochondrial TA proteins. Accordingly, deletion of PEX19 results in: (1) growth defect under respiration conditions, (2) alteration in mitochondrial morphology, (3) reduced steady-state levels of the mitochondrial TA proteins Fis1 and Gem1, and (4) hampered in organello import of the TA proteins Fis1 and Gem1. Furthermore, recombinant Pex19 can bind directly the TA proteins Fis1 and Gem1. Collectively, this work identified the first factors that are involved in the biogenesis of mitochondrial TA proteins and uncovered an unexpected function of Pex19.

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

Cited by 65 publications

References 55 publications

Substrate relay in an Hsp70‐cochaperone cascade safeguards tail‐anchored membrane protein targeting

Substrate relay in an Hsp70‐cochaperone cascade safeguards tail‐anchored membrane protein targeting

The GET pathway can increase the risk of mitochondrial outer membrane proteins to be mistargeted to the ER

Pex19 is involved in importing dually targeted tail‐anchored proteins to both mitochondria and peroxisomes

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