scholarly journals Dual Independent Roles of the p24 Complex in Selectivity of Secretory Cargo Export from the Endoplasmic Reticulum

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1295
Author(s):  
Sergio Lopez ◽  
Ana Maria Perez-Linero ◽  
Javier Manzano-Lopez ◽  
Susana Sabido-Bozo ◽  
Alejandro Cortes-Gomez ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Transport ◽  
Retrograde Transport ◽  
Secretory Proteins ◽  
Dependent Manner ◽  
Cellular Mechanisms ◽  
Export Pathway ◽  
Additional Layer ◽  
Cargo Receptor ◽  
Er Export

The cellular mechanisms that ensure the selectivity and fidelity of secretory cargo protein transport from the endoplasmic reticulum (ER) to the Golgi are still not well understood. The p24 protein complex acts as a specific cargo receptor for GPI-anchored proteins by facilitating their ER exit through a specialized export pathway in yeast. In parallel, the p24 complex can also exit the ER using the general pathway that exports the rest of secretory proteins with their respective cargo receptors. Here, we show biochemically that the p24 complex associates at the ER with other cargo receptors in a COPII-dependent manner, forming high-molecular weight multireceptor complexes. Furthermore, live cell imaging analysis reveals that the p24 complex is required to retain in the ER secretory cargos when their specific receptors are absent. This requirement does not involve neither the unfolded protein response nor the retrograde transport from the Golgi. Our results suggest that, in addition to its role as a cargo receptor in the specialized GPI-anchored protein pathway, the p24 complex also plays an independent role in secretory cargo selectivity during its exit through the general ER export pathway, preventing the non-selective bulk flow of native secretory cargos. This mechanism would ensure receptor-regulated cargo transport, providing an additional layer of regulation of secretory cargo selectivity during ER export.

scholarly journals The yeast p24 complex regulates GPI-anchored protein transport and quality control by monitoring anchor remodeling

2011 ◽  
Vol 22 (16) ◽  
pp. 2924-2936 ◽  
Author(s):  
Guillaume A. Castillon ◽  
Auxiliadora Aguilera-Romero ◽  
Javier Manzano-Lopez ◽  
Sharon Epstein ◽  
Kentaro Kajiwara ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Cell Surface ◽  
Intracellular Transport ◽  
Protein Transport ◽  
Eukaryotic Cells ◽  
Secretory Proteins ◽  
Dependent Manner ◽  
Gpi Anchor ◽  
The Status

Glycosylphosphatidylinositol (GPI)-anchored proteins are secretory proteins that are attached to the cell surface of eukaryotic cells by a glycolipid moiety. Once GPI anchoring has occurred in the lumen of the endoplasmic reticulum (ER), the structure of the lipid part on the GPI anchor undergoes a remodeling process prior to ER exit. In this study, we provide evidence suggesting that the yeast p24 complex, through binding specifically to GPI-anchored proteins in an anchor-dependent manner, plays a dual role in their selective trafficking. First, the p24 complex promotes efficient ER exit of remodeled GPI-anchored proteins after concentration by connecting them with the COPII coat and thus facilitates their incorporation into vesicles. Second, it retrieves escaped, unremodeled GPI-anchored proteins from the Golgi to the ER in COPI vesicles. Therefore the p24 complex, by sensing the status of the GPI anchor, regulates GPI-anchored protein intracellular transport and coordinates this with correct anchor remodeling.

scholarly journals Requirement for Neo1p in Retrograde Transport from the Golgi Complex to the Endoplasmic Reticulum

2003 ◽  
Vol 14 (12) ◽  
pp. 4971-4983 ◽  
Author(s):  
Zhaolin Hua ◽  
Todd R. Graham
Keyword(s):  
Endoplasmic Reticulum ◽  
Golgi Complex ◽  
Secretory Pathway ◽  
Protein Transport ◽  
Retrograde Transport ◽  
Transport Pathway ◽  
Transport Defect ◽  
Copii Vesicles ◽  
P Type ◽  
Adp Ribosylation Factor

Neo1p from Saccharomyces cerevisiae is an essential P-type ATPase and potential aminophospholipid translocase (flippase) in the Drs2p family. We have previously implicated Drs2p in protein transport steps in the late secretory pathway requiring ADP-ribosylation factor (ARF) and clathrin. Here, we present evidence that epitope-tagged Neo1p localizes to the endoplasmic reticulum (ER) and Golgi complex and is required for a retrograde transport pathway between these organelles. Using conditional alleles of NEO1, we find that loss of Neo1p function causes cargo-specific defects in anterograde protein transport early in the secretory pathway and perturbs glycosylation in the Golgi complex. Rer1-GFP, a protein that cycles between the ER and Golgi complex in COPI and COPII vesicles, is mislocalized to the vacuole in neo1-ts at the nonpermissive temperature. These phenotypes suggest that the anterograde protein transport defect is a secondary consequence of a defect in a COPI-dependent retrograde pathway. We propose that loss of lipid asymmetry in the cis Golgi perturbs retrograde protein transport to the ER.

scholarly journals The ADP Ribosylation Factor-Nucleotide Exchange Factors Gea1p and Gea2p Have Overlapping, but Not Redundant Functions in Retrograde Transport from the Golgi to the Endoplasmic Reticulum

2001 ◽  
Vol 12 (4) ◽  
pp. 1035-1045 ◽  
Author(s):  
Anne Spang ◽  
Johannes M. Herrmann ◽  
Susan Hamamoto ◽  
Randy Schekman
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Transport ◽  
Retrograde Transport ◽  
Guanine Nucleotide Exchange Factors ◽  
Temperature Sensitive ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Membrane Bound

The activation of the small ras-like GTPase Arf1p requires the action of guanine nucleotide exchange factors. Four Arf1p guanine nucleotide exchange factors have been identified in yeast: Sec7p, Syt1p, Gea1p, and its homologue Gea2p. We identifiedGEA2 as a multicopy suppressor of asec21-3 temperature-sensitive mutant.SEC21 encodes the γ-subunit of coatomer, a heptameric protein complex that together with Arf1p forms the COPI coat.GEA1 and GEA2 have at least partially overlapping functions, because deletion of either gene results in no obvious phenotype, whereas the double null mutant is inviable. Conditional mutants defective in both GEA1 andGEA2 accumulate endoplasmic reticulum and Golgi membranes under restrictive conditions. The two genes do not serve completely overlapping functions because a Δgea1Δarf1 mutant is not more sickly than a Δarf1 strain, whereas Δgea2Δarf1 is inviable. Biochemical experiments revealed similar distributions and activities for the two proteins. Gea1p and Gea2p exist both in membrane-bound and in soluble forms. The membrane-bound forms, at least one of which, Gea2p, can be visualized on Golgi structures, are both required for vesicle budding and protein transport from the Golgi to the endoplasmic reticulum. In contrast, Sec7p, which is required for protein transport within the Golgi, is not required for retrograde protein trafficking.

scholarly journals Efect of Sec61 interaction with Mpd1 on Endoplasmic Reticulum- Associated Degradation

2018 ◽  
Author(s):  
Fábio Pereira ◽  
Mandy Rettel ◽  
Frank Stein ◽  
Mikhail M. Savitski ◽  
Ian Collinson ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Import ◽  
Retrograde Transport ◽  
Secretory Proteins ◽  
Chemical Crosslinking ◽  
Endoplasmic Reticulum Associated Degradation ◽  
Channel Opening ◽  
Interaction Partners ◽  
Sec61 Channel

AbstractProteins that misfold in the endoplasmic reticulum (ER) are transported back to the cytosol for ER-associated degradation (ERAD). The Sec61 channel is one of the candidates for the retrograde transport conduit. Channel opening from the ER lumen must be triggered by ERAD factors and substrates. Here we identified new lumenal interaction partners of Sec61 by chemical crosslinking and mass spectrometry. In addition to known Sec61 interactors we detected ERAD factors including Cue1, Ubc6, Ubc7, Asi3, and Mpd1. We show that the CPY* ERAD factor Mpd1 binds to the lumenal Sec61 hinge region. Deletion of the Mpd1 binding site reduced the interaction between both proteins and caused an ERAD defect specific for CPY* without affecting protein import into the ER or ERAD of other substrates. Our data suggest that Mpd1 binding to Sec61 is a prerequisite for CPY* ERAD and confirm a role of Sec61 in ERAD of misfolded secretory proteins.

scholarly journals Signal sequence-dependent function of the TRAM protein during early phases of protein transport across the endoplasmic reticulum membrane.

1996 ◽  
Vol 134 (1) ◽  
pp. 25-35 ◽  
Author(s):  
S Voigt ◽  
B Jungnickel ◽  
E Hartmann ◽  
T A Rapoport
Keyword(s):  
Protein Transport ◽  
Signal Sequence ◽  
Chain Complex ◽  
Secretory Proteins ◽  
Endoplasmic Reticulum Membrane ◽  
Dependent Manner ◽  
Hydrophobic Core ◽  
Sequence Dependent ◽  
Nascent Chain ◽  
Er Membrane

Cotranslational translocation of proteins across the mammalian ER membrane involves, in addition to the signal recognition particle receptor and the Sec61p complex, the translocating chain-associating membrane (TRAM) protein, the function of which is still poorly understood. Using reconstituted proteoliposomes, we show here that the translocation of most, but not all, secretory proteins requires the function of TRAM. Experiments with hybrid proteins demonstrate that the structure of the signal sequence determines whether or not TRAM is needed. Features that distinguish TRAM-dependent and -independent signal sequences include the length of their charged, NH2-terminal region and the structure of their hydrophobic core. In cases where TRAM is required for translocation, it is not needed for the initial interaction of the ribosome/nascent chain complex with the ER membrane but for a subsequent step inside the membrane in which the nascent chain is inserted into the translocation site in a protease-resistant manner. Thus, TRAM functions in a signal sequence-dependent manner at a critical, early phase of the translocation process.

Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease. 3. Orchestrating the unfolded protein response in oncogenesis: an update

2014 ◽  
Vol 307 (10) ◽  
pp. C901-C907 ◽  
Author(s):  
Serge N. Manié ◽  
Justine Lebeau ◽  
Eric Chevet
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Dependent Manner ◽  
Cellular Mechanisms ◽  
Unfolded Protein ◽  
Stress Sensors ◽  
Plasma Membrane Receptor ◽  
The Unfolded Protein Response ◽  
Stress Dependent ◽  
Protein Response

The endoplasmic reticulum (ER)-induced unfolded protein response (UPR) is an adaptive mechanism that is activated upon accumulation of misfolded proteins in the ER and aims at restoring ER homeostasis. In the past 10 years, the UPR has emerged as an important actor in the different phases of tumor growth. The UPR is transduced by three major ER resident stress sensors, which are protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme-1 (IRE1). The signaling pathways elicited by those stress sensors have connections with metabolic pathways and with other plasma membrane receptor signaling networks. As such, the ER has an essential position as a signal integrator in the cell and is instrumental in the different phases of tumor progression. Herein, we describe and discuss the characteristics of an integrated signaling network that might condition the UPR biological outputs in a tissue- or stress-dependent manner. We discuss these issues in the context of the pathophysiological roles of UPR signaling in cancers.

scholarly journals Regulation of Protein Transport from the Golgi Complex to the Endoplasmic Reticulum by CDC42 and N-WASP

2002 ◽  
Vol 13 (3) ◽  
pp. 866-879 ◽  
Author(s):  
Ana Luna ◽  
Olga B. Matas ◽  
José Angel Martı́nez-Menárguez ◽  
Eugenia Mato ◽  
Juan M. Durán ◽  
...  
Keyword(s):  
Golgi Complex ◽  
Mammalian Cells ◽  
Protein Transport ◽  
Retrograde Transport ◽  
Small Gtpase ◽  
Actin Dynamics ◽  
Mutant Form ◽  
Dependent Manner ◽  
Wild Type ◽  
Kdel Receptor

Actin is involved in the organization of the Golgi complex and Golgi-to-ER protein transport in mammalian cells. Little, however, is known about the regulation of the Golgi-associated actin cytoskeleton. We provide evidence that Cdc42, a small GTPase that regulates actin dynamics, controls Golgi-to-ER protein transport. We located GFP-Cdc42 in the lateral portions of Golgi cisternae and in COPI-coated and noncoated Golgi-associated transport intermediates. Overexpression of Cdc42 and its activated form Cdc42V12 inhibited the retrograde transport of Shiga toxin from the Golgi complex to the ER, the redistribution of the KDEL receptor, and the ER accumulation of Golgi-resident proteins induced by the active GTP-bound mutant of Sar1 (Sar1[H79G]). Coexpression of wild-type or activated Cdc42 and N-WASP also inhibited Golgi-to-ER transport, but this was not the case in cells expressing Cdc42V12 and N-WASP(ΔWA), a mutant form of N-WASP that lacks Arp2/3 binding. Furthermore, Cdc42V12 recruited GFP-N-WASP to the Golgi complex. We therefore conclude that Cdc42 regulates Golgi-to-ER protein transport in an N-WASP–dependent manner.

scholarly journals Protein transport from endoplasmic reticulum to the Golgi complex can occur during meiotic metaphase in Xenopus oocytes.

1989 ◽  
Vol 109 (4) ◽  
pp. 1439-1444 ◽  
Author(s):  
A Ceriotti ◽  
A Colman
Keyword(s):  
Endoplasmic Reticulum ◽  
Mammalian Cells ◽  
Intracellular Transport ◽  
Xenopus Oocytes ◽  
Protein Transport ◽  
Surrounding Medium ◽  
Meiotic Metaphase ◽  
Secretory Proteins ◽  
Yeast Saccharomyces Cerevisiae ◽  
Residual Protein

We have previously shown that Xenopus oocytes arrested at second meiotic metaphase lost their characteristic multicisternal Golgi apparati and cannot secrete proteins into the surrounding medium. In this paper, we extend these studies to ask whether intracellular transport events affecting the movement of secretory proteins from the endoplasmic reticulum to the Golgi apparatus are also similarly inhibited in such oocytes. Using the acquisition of resistance to endoglycosidase H (endo H) as an assay for movement to the Golgi, we find that within 6 h, up to 66% of the influenza virus membrane protein, hemagglutinin (HA), synthesized from injected synthetic RNA, can move to the Golgi apparati in nonmatured oocytes; indeed after longer periods some correctly folded HA can be detected at the cell surface where it distributes in a nonpolarized fashion. In matured oocytes, up to 49% of the HA becomes endo H resistant in the same 6-h period. We conclude that movement from the endoplasmic reticulum to the Golgi can occur in matured oocytes despite the dramatic fragmentation of the Golgi apparati that we observe to occur on maturation. This observation of residual protein movement during meiotic metaphase contrasts with the situation at mitotic metabphase in cultured mammalian cells where all movement ceases, but resembles that in the budding yeast Saccharomyces cerevisiae where transport is unaffected.

scholarly journals The GTPase Arf1p and the ER to Golgi cargo receptor Erv14p cooperate to recruit the golgin Rud3p to the cis-Golgi

2004 ◽  
Vol 167 (2) ◽  
pp. 281-292 ◽  
Author(s):  
Alison K. Gillingham ◽  
Amy Hin Yan Tong ◽  
Charles Boone ◽  
Sean Munro
Keyword(s):  
Endoplasmic Reticulum ◽  
Genetic Interaction ◽  
Coiled Coil ◽  
Terminal Region ◽  
Human Protein ◽  
Dependent Manner ◽  
Terminal Domain ◽  
Cargo Receptor ◽  
The One

Rud3p is a coiled-coil protein of the yeast cis-Golgi. We find that Rud3p is localized to the Golgi via a COOH-terminal domain that is distantly related to the GRIP domain that recruits several coiled-coil proteins to the trans-Golgi by binding the small Arf-like GTPase Arl1p. In contrast, Rud3p binds to the GTPase Arf1p via this COOH-terminal “GRIP-related Arf-binding” (GRAB) domain. Deletion of RUD3 is lethal in the absence of the Golgi GTPase Ypt6p, and a screen of other mutants showing a similar genetic interaction revealed that Golgi targeting of Rud3p also requires Erv14p, a cargo receptor that cycles between the endoplasmic reticulum and Golgi. The one human protein with a GRAB domain, GMAP-210 (CEV14/Trip11/Trip230), is known to be on the cis-Golgi, but the COOH-terminal region that contains the GRAB domain has been reported to bind to centrosomes and γ-tubulin (Rios, R.M, A. Sanchis, A.M. Tassin, C. Fedriani, and M. Bornens. 2004. Cell. 118:323–335). In contrast, we find that this region binds to the Golgi in a GRAB domain–dependent manner, suggesting that GMAP-210 may not link the Golgi to γ-tubulin and centrosomes.

scholarly journals LTK is an ER-resident receptor tyrosine kinase that regulates secretion

2019 ◽  
Author(s):  
Federica G. Centonze ◽  
Veronika Reiterer ◽  
Karsten Nalbach ◽  
Kota Saito ◽  
Krzysztof Pawlowski ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Receptor Tyrosine Kinase ◽  
Secretory Proteins ◽  
Golgi Transport ◽  
Er Exit Sites ◽  
Local Signaling ◽  
Er Export ◽  
Pharmacologic Inhibition

AbstractThe endoplasmic reticulum (ER) is a key regulator of cellular proteostasis because it controls folding, sorting and degradation of secretory proteins. Much has been learned about how environmentally triggered signaling pathways regulate ER function, but only little is known about local signaling at the ER. The identification of ER-resident signaling molecules will help gain a deeper understanding of the regulation of ER function and thus of proteostasis. Here, we show that leukocyte tyrosine kinase (LTK) is an ER-resident receptor tyrosine kinase. Depletion of LTK as well as its pharmacologic inhibition reduces the number of ER exit sites and slows ER-to-Golgi transport. Furthermore, we show that LTK interacts with and phosphorylates Sec12. Expression of a phosphoablating mutant of Sec12 reduces the efficiency of ER export. Thus, LTK-to-Sec12 signaling represents the first example of an ER-resident signaling module the potential to regulate proteostasis.

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