Role of EDEM in the Release of Misfolded Glycoproteins from the Calnexin Cycle

Molinari, Maurizio; Calanca, Verena; Galli, Carmela; Lucca, Paola; Paganetti, Paolo

doi:10.1126/science.1079474

Cited by 438 publications

(364 citation statements)

References 13 publications

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“…EDEM1 presumably possesses mannosidase activity that trims the C branch of N-glycans on misfolded proteins; however, that activity is apparently not required for ERAD acceleration because mutant EDEM1 that lacks the putative active site for mannosidase is still able to accelerate ERAD (Hosokawa et al 2001(Hosokawa et al , 2006(Hosokawa et al , 2010bMolinari et al 2003;Oda et al 2003;Olivari et al 2006). EDEM2 also promotes ERAD, even though it has no enzymatic activity (Mast et al 2005;Olivari et al 2005).…”

Section: Recognition and Targetingmentioning

confidence: 99%

Protein Folding and Quality Control in the ER

Araki

Nagata

2011

Cold Spring Harbor Perspectives in Biology

317

285

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The endoplasmic reticulum (ER) uses an elaborate surveillance system called the ER quality control (ERQC) system. The ERQC facilitates folding and modification of secretory and membrane proteins and eliminates terminally misfolded polypeptides through ER-associated degradation (ERAD) or autophagic degradation. This mechanism of ER protein surveillance is closely linked to redox and calcium homeostasis in the ER, whose balance is presumed to be regulated by a specific cellular compartment. The potential to modulate proteostasis and metabolism with chemical compounds or targeted siRNAs may offer an ideal option for the treatment of disease.

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Section: Recognition and Targetingmentioning

confidence: 99%

Protein Folding and Quality Control in the ER

Araki

Nagata

2011

Cold Spring Harbor Perspectives in Biology

317

285

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“…If, despite repeated cycles of deglycosylation-reglucosylation, a glycoprotein fails to fold properly, it is retained in the ER and eventually degraded. Targeting of misfolded proteins to the ER-associated degradation (ERAD) is facilitated by lectin EDEM (57). ER retention and subsequent ERAD are critical for normal cellular function because they prevent accumulation of dysfunctional proteins in the cell (39,40,77).…”

Section: Role Of N-glycans In Protein Folding Stability and Qualitymentioning

confidence: 99%

Role of N-glycosylation in trafficking of apical membrane proteins in epithelia

Vagin

Kraut²,

Sachs³

2009

American Journal of Physiology-Renal Physiology

177

157

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ized distribution of plasma membrane transporters and receptors in epithelia is essential for vectorial functions of epithelia. This polarity is maintained by sorting of membrane proteins into apical or basolateral transport containers in the transGolgi network and/or endosomes followed by their delivery to the appropriate plasma membrane domains. Sorting depends on the recognition of sorting signals in proteins by specific sorting machinery. In the present review, we summarize experimental evidence for and against the hypothesis that N-glycans attached to the membrane proteins can act as apical sorting signals. Furthermore, we discuss the roles of N-glycans in the apical sorting event per se and their contribution to folding and quality control of glycoproteins in the endoplasmic reticulum or retention of glycoproteins in the plasma membrane. Finally, we review existing hypotheses on the mechanism of apical sorting and discuss the potential roles of the lectins, VIP36 and galectin-3, as putative apical sorting receptors. apical sorting; apical membrane retention; H-K-ATPase ␤-subunit; lectin EPITHELIAL CELLS CARRY OUT vectorial transport that requires polarized distribution of transporters and receptors to apical or basolateral membrane domains. These domains are separated by tight junctions that connect neighboring cells in the epithelial monolayer and act as diffusion barriers to prevent mixing of apical and basolateral membrane components (22). Asymmetric distribution of plasma membrane proteins is accomplished by their sorting into apical and basolateral containers in the trans-Golgi network (TGN) and/or endosomes followed by vectorial transport of these containers and insertion and retention of the proteins in the appropriate plasma membrane domains. Sorting depends on recognition of apical and basolateral sorting signals within the proteins by cellular sorting machinery (20,58,59,75,76).Numerous studies have indicated that both O-and N-glycans attached to the extracellular domains of some membrane proteins are important for apical location of these proteins. This review will focus on the role of N-glycans in polarized distribution of plasma membrane proteins in epithelia. The role of O-glycans in apical sorting has been described in several recent excellent reviews (18, 71) and will not be discussed further here.A putative role of N-glycans as apical sorting signals was postulated more than 10 years ago (24, 31). However, this hypothesis remains controversial primarily because N-glycans are important for the processes that precede or follow the actual sorting event, such as protein folding, quality control, endoplasmic reticulum (ER)-associated degradation, ER-to-Golgi trafficking, and retention of glycoproteins in the apical membrane. Therefore, merely examining the effect of altering the number or the nature of N-linked glycans on the relative abundance of the glycoprotein in the apical membrane, as has been done in many of the studies reported, does not allow one to distinguish between effects on apica...

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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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Role of EDEM in the Release of Misfolded Glycoproteins from the Calnexin Cycle

Cited by 438 publications

References 13 publications

Protein Folding and Quality Control in the ER

Protein Folding and Quality Control in the ER

Role of N-glycosylation in trafficking of apical membrane proteins in epithelia

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

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