Yos9 Protein Is Essential for Degradation of Misfolded Glycoproteins and May Function as Lectin in ERAD

Szathmary, Reka; Bielmann, Regula; Niță-Lazăr, Mihai; Burda, Patricie; Jakob, Claude A.

doi:10.1016/j.molcel.2005.08.015

Cited by 186 publications

(168 citation statements)

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“…The glycosylation status of these proteins provides cues as to the progression of folding This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E07-07-0674) on April 9, 2008. (Molinari et al, 2003;Oda et al, 2003;Bhamidipati et al, 2005;Szathmary et al, 2005). ER-degradation enhancing alphamannosidase like protein (EDEM), an XBP-1 target gene encoding a lectin, detects inappropriately trimmed glycans and redirects the misfolded glycoprotein from the calnexin/calreticulin folding cycle to the degradation pathway.…”

Section: Introductionmentioning

confidence: 99%

ERdj4 and ERdj5 Are Required for Endoplasmic Reticulum-associated Protein Degradation of Misfolded Surfactant Protein C

Dong

Bridges

Apsley

et al. 2008

MBoC

144

171

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Mutations in the SFTPC gene associated with interstitial lung disease in human patients result in misfolding, endoplasmic reticulum (ER) retention, and degradation of the encoded surfactant protein C (SP-C) proprotein. In this study, genes specifically induced in response to transient expression of two disease-associated mutations were identified by microarray analyses. Immunoglobulin heavy chain binding protein (BiP) and two heat shock protein 40 family members, endoplasmic reticulum-localized DnaJ homologues ERdj4 and ERdj5, were significantly elevated and exhibited prolonged and specific association with the misfolded proprotein; in contrast, ERdj3 interacted with BiP, but it did not associate with either wild-type or mutant SP-C. Misfolded SP-C, ERdj4, and ERdj5 coprecipitated with p97/VCP indicating that the cochaperones remain associated with the misfolded proprotein until it is dislocated to the cytosol. Knockdown of ERdj4 and ERdj5 expression increased ER retention and inhibited degradation of misfolded SP-C, but it had little effect on the wild-type protein. Transient expression of ERdj4 and ERdj5 in X-box binding protein 1 ؊/؊ mouse embryonic fibroblasts substantially restored rapid degradation of mutant SP-C proprotein, whereas transfection of HPD mutants failed to rescue SP-C endoplasmic reticulum-associated protein degradation. ERdj4 and ERdj5 promote turnover of misfolded SP-C and this activity is dependent on their ability to stimulate BiP ATPase activity.

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Section: Introductionmentioning

confidence: 99%

ERdj4 and ERdj5 Are Required for Endoplasmic Reticulum-associated Protein Degradation of Misfolded Surfactant Protein C

Dong

Bridges

Apsley

et al. 2008

MBoC

144

171

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“…This is also reflected by an increase in the specific production titers compared to the Δyos9 deletion strain. A reduced clearance had already been reported for CPY* and other artificial ERAD substrates (Szathmary et al 2005;Clerc et al 2009). …”

Section: Discussionmentioning

confidence: 60%

“…These substrates have been used to gain information on the roles of, among others, Yos9p (Szathmary et al 2005;Benitez et al 2011),…”

Section: Discussionmentioning

confidence: 99%

“…In addition, IgG secretion was increased in the Δalg3 strains, a genotype which is considered not to produce the glycan signal for ERAD. It has been shown that removal of a mannose by Htm1p is required for efficient binding of ERAD targeted proteins to Yos9p (Szathmary et al 2005;Clerc et al 2009). Therefore, this could imply that the slowly folding IgG protein escape from degradation through ERAD in the Δhtm1 background, giving it more time to fold and be secreted.…”

Section: Discussionmentioning

confidence: 99%

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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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“…A mannosidaselike protein Mnl1p recognizes a single isomer of Man 8 GlcNAc 2 glycan of misfolded glycoprotein, and cuts off a terminal 1,2-alpha-mannose residue from the C-chain to generate Man 7 GlcNAc 2 glycan (Figure 2 et Jakob et al, 2001;Nakatsukasa et al, 2001). Lectin Yos9p recognizes the generated 1,6-alpha-linked mannose terminal of Man 7 GlcNAc 2 glycan and then accelerates the ERAD (Buschhorn et al, 2004;Clerc et al, 2009;Friedmann et al, 2002;Gauss et al, 2006;Kanehara et al, 2007;Szathmary et al, 2005). In mns1 cells, Man 9 -GlcNAc 2 glycan is not processed to Man 8 GlcNAc 2 because of lack of Mns1p and is not recognized by Mnl1p.…”

Section: Hm-1-resistant Phenotypes Of Mns1 Do Not Participate In Endomentioning

confidence: 99%

Genome‐wide screen of Saccharomyces cerevisiae for killer toxin HM‐1 resistance

Miyamoto

Furuichi

Komiyama

2010

Yeast

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We screened a set of Saccharomyces cerevisiae deletion mutants for resistance to killer toxin HM-1, which kills susceptible yeasts through inhibiting 1,3-beta-glucan synthase. By using HM-1 plate assay, we found that eight gene-deletion mutants had higher HM-1-resistance compared with the wild-type. Among these eight genes, five -ALG3, CAX4, MNS1, OST6 and YBL083C -were associated with N -glycan formation and maturation. The ALG3 gene has been shown before to be highly resistant to HM-1. The YBL083C gene may be a dubious open reading frame that overlaps partially the ALG3 gene. The deletion mutant of the MNS1 gene that encodes 1,2-alpha-mannosidase showed with a 13-fold higher HM-1 resistance compared with the wild-type. By HM-1 binding assay, the yeast plasma membrane fraction of alg3 and mns1 cells had less binding ability compared with wild-type cells. These results indicate that the presence of the terminal 1,3-alpha-linked mannose residue of the B-chain of the N -glycan structure is essential for interaction with HM-1. A deletion mutant of aquaglyceroporin Fps1p also showed increased HM-1 resistance. A deletion mutant of osmoregulatory mitogen-activated protein kinase Hog1p was more sensitive to HM-1, suggesting that high-osmolarity glycerol pathways plays an important role in the compensatory response to HM-1 action.

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Yos9 Protein Is Essential for Degradation of Misfolded Glycoproteins and May Function as Lectin in ERAD

Cited by 186 publications

References 74 publications

ERdj4 and ERdj5 Are Required for Endoplasmic Reticulum-associated Protein Degradation of Misfolded Surfactant Protein C

ERdj4 and ERdj5 Are Required for Endoplasmic Reticulum-associated Protein Degradation of Misfolded Surfactant Protein C

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

Genome‐wide screen of Saccharomyces cerevisiae for killer toxin HM‐1 resistance

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