Yos9p and Hrd1p mediate ER retention of misfolded proteins for ER-associated degradation

Izawa, Toshiaki; Nagai, Hiroyuki; Endo, Toshiya; Nishikawa, Shuh-ichi

doi:10.1091/mbc.e11-08-0722

Cited by 27 publications

(22 citation statements)

References 52 publications

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“…with carboxypeptidase Y star-green fluorescent protein (CPY*-GFP), a known BiP substrate (Izawa et al, 2012), when it was expressed from a transgene in Arabidopsis (see Supplemental Figure 3 online). Client proteins can be released from BiP by ADP/ATP exchange in BiP's N-terminal nucleotide binding domain .…”

Section: Characteristics Of Bip Binding To Bzip28mentioning

confidence: 99%

BINDING PROTEIN Is a Master Regulator of the Endoplasmic Reticulum Stress Sensor/Transducer bZIP28 in Arabidopsis

et al. 2013

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BINDING PROTEIN (BiP) is a major chaperone in the endoplasmic reticulum (ER) lumen, and this study shows that BiP binds to the C-terminal tail of the stress sensor/transducer bZIP28, a membrane-associated transcription factor, retaining it in the ER under unstressed conditions. In response to ER stress, BiP dissociates from bZIP28, allowing it to be mobilized from the ER to the Golgi where it is proteolytically processed and released to enter the nucleus. Under unstressed conditions, BiP binds to bZIP28 as it binds to other client proteins, through its substrate binding domain. BiP dissociates from bZIP28 even when bZIP28's exit from the ER or its release from the Golgi is blocked. Both BiP1 and BiP3 bind bZIP28, and overexpression of either BiP detains bZIP28 in the ER under stress conditions. A C-terminally truncated mutant of bZIP28 eliminating most of the lumenal domain does not bind BiP and is not retained in the ER under unstressed conditions. BiP binding sites in the C-terminal tail of bZIP28 were identified in a phage display system. BiP was found to bind to intrinsically disordered regions on bZIP28's lumen-facing tail. Thus, the dissociation of BiP from the C-terminal tail of bZIP28 is a major switch that activates one arm of the unfolded protein response signaling pathway in plants.

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Section: Characteristics Of Bip Binding To Bzip28mentioning

confidence: 99%

BINDING PROTEIN Is a Master Regulator of the Endoplasmic Reticulum Stress Sensor/Transducer bZIP28 in Arabidopsis

et al. 2013

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“…Also for the HRD1 deletion a delayed degradation of ERAD substrates has been found (Benitez et al 2011). In addition, misfolded substrates have shown to have an increased ER retention when HRD1 is deleted (Izawa et al 2012), which might contribute to the increased IgG load at the end of the clearance assay. Htm1p and Yos9p are responsible for generating and recognizing the glycan degradation signal in ERAD, respectively.…”

Section: Discussionmentioning

confidence: 99%

Analysis of antibody production in Saccharomyces cerevisiae: effects of ER protein quality control disruption

Ruijter

Frey

2015

Appl Microbiol Biotechnol

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One of the main limitations for heterologous protein production in the yeast Saccharomyces cerevisiae is the protein folding capacity in the endoplasmic reticulum (ER). Accumulation of unfolded proteins triggers the unfolded protein response (UPR), which resolves the stress by increasing the capacity for protein folding and removal of unfolded proteins by the ER associated degradation (ERAD) system. In order to analyse the influence of ERAD on production of a human IgG, we disrupted ERAD at different stages by deletion of the HTM1, YOS9, HRD1, HRD3 or UBC7 gene, with or without a disruption of the UPR by deletion of the IRE1 gene. All deletion strains were viable and did not exhibit a growth phenotype under normal growth conditions. Deletion of HTM1 resulted in a small increase in antibody production, whereas a small decrease in antibody production was observed in the Δhrd1, Δhrd3 and Δubc7 yeast strains, and a stronger decrease in the Δyos9 yeast strain. Deletion of the IRE1 gene had contrasting effects in the ERAD mutants, with a strongly decreased production in wild type cells and partially reversed effects in combination with the Δhtm1 or the Δyos9 deletions. In order to study IgG clearance from the ER, an assay was developed using the inhibitory effect of glucose on the GAL1 promoter that is driving IgG expression. The Δyos9Δire1and Δhtm1Δire1 strains showed a delayed IgG clearance from the cells, showing that removal of components for the generation and recognition of the glycan signal needed for ERAD mediated protein degradation might increase the IgG ER residence time.3

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“…9) Although both CPY*-CPY and CPY*-CPY* were targeted to the ERAD, CPY-CPY* exited from the ER, similarly to the CPY-CPY protein, thereby escaping from the ERAD. This was due to decreased association of CPY-CPY* with Yos9 as well as a concomitant recognition of the folded CPY domain as an ER exit signal by the export receptor, Erv29.…”

Section: Discussionmentioning

confidence: 99%

“…Retention of misfolded proteins in the ER can be attributed to binding of ERAD machinery such as molecular chaperones and lectins to exposed hydrophobic patches and immature N-glycans on misfolded proteins, respectively. [6][7][8][9] Proteins can be in equilibrium between the unfolded and the folded state, and the lower their thermodynamic stability, the higher the chance of exposing the hydrophobic regions where chaperones bind. Another aspect of ER retention of misfolded proteins is loss of the ER exit signal.…”

mentioning

confidence: 99%

Fusion of an intact secretory protein permits a misfolded protein to exit from the endoplasmic reticulum in yeast

Suyama

Hori

Gomi

et al. 2014

Bioscience, Biotechnology, and Biochemistry

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Upon exit from the endoplasmic reticulum (ER), the nascent polypeptides of secretory proteins undergo sorting events. If properly folded, they are directly or indirectly recognized by the coat proteins of budding vesicles for forward transport, while unfolded or misfolded proteins are retained in the ER by a quality control mechanism. To gain insight into the interplay between ER export and ER quality control, we fused a secretory protein invertase to the C-terminus of mutated carboxypeptidase Y (CPY*), a model ER-associated degradation (ERAD) substrate in Saccharomyces cerevisiae. This substrate, designated CPY*-Inv, was largely exported from the ER, although it was fully recognized by the ERAD-related lectin, Yos9, and hence degraded by the ERAD when it remained in the ER. CPY*-Inv relied primarily on the p24 complex, a putative ER export receptor for invertase, for escape from ERAD, suggesting that the ERAD and the ER export of soluble secretory proteins are competitive.

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Yos9p and Hrd1p mediate ER retention of misfolded proteins for ER-associated degradation

Cited by 27 publications

References 52 publications

BINDING PROTEIN Is a Master Regulator of the Endoplasmic Reticulum Stress Sensor/Transducer bZIP28 in Arabidopsis

BINDING PROTEIN Is a Master Regulator of the Endoplasmic Reticulum Stress Sensor/Transducer bZIP28 in Arabidopsis

Analysis of antibody production in Saccharomyces cerevisiae: effects of ER protein quality control disruption

Fusion of an intact secretory protein permits a misfolded protein to exit from the endoplasmic reticulum in yeast

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