EDEM As an Acceptor of Terminally Misfolded Glycoproteins Released from Calnexin

Oda, Yusuke; Hosokawa, Nobuko; Wada, Ikuo; Nagata, Kazuhiro

doi:10.1126/science.1079181

Cited by 422 publications

(338 citation statements)

References 25 publications

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“…1D). Bypass of the Cnx cycle has been shown to emancipate glycoprotein degradation from the intralumenal level of EDEM (16) because EDEM operates as an extraction factor for terminally misfolded glycoproteins from the Cnx cycle (15,16). Taken together, these data therefore confirm that the GERAD phenotype of Xbp1 Ϫ/Ϫ MEF is indeed mainly related to the suboptimal level of EDEM.…”

Section: Xbp1supporting

confidence: 75%

EDEM Contributes to Maintenance of Protein Folding Efficiency and Secretory Capacity

Eriksson¹,

Vago

Calanca³

et al. 2004

Journal of Biological Chemistry

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A stringent quality control process selects misfolded polypeptides generated in the endoplasmic reticulum (ER) for ER-associated degradation (ERAD). Here we assessed the maintenance of efficient glycoprotein folding in cells with defective ERAD caused by lack of adaptation of the intralumenal level of ER degradationenhancing ␣-mannosidase-like protein (EDEM) to an increase in the ER cargo load. When these cells were converted into factories for production of high levels of human ␤-secretase, maturation of this N-glycosylated aspartic protease progressed as in wild-type cells initially to gradually become less efficient. Up-regulation of EDEM to strengthen the ERAD machinery (but not up-regulation of calnexin to reinforce the folding machinery) was instrumental in maintaining folding efficiency and secretory capacity. Our data underscore the important role that the degradation machinery plays in maintaining a functional folding environment in the ER.Only a fraction of the polypeptide chains expressed in the ER 1 is transported to its final destination. A stringent quality control process prevents export of orphan subunits of oligomeric complexes, folding-incompetent products of mutated genes, and by-products of protein biosynthesis that do not acquire the native conformation (1-3). Polypeptides that do not pass quality control are either retained by the ER chaperone network to be used for further folding attempts or are sorted out for cytosolic degradation. The mechanisms regulating ER quality control are better understood for N-glycosylated polypeptides. N-glycans are added to asparagines in nascent chains as pre-assembled tri-antennary oligosaccharides composed of three terminal glucoses, nine mannoses, and two Nacetylglucosamines. The two outermost glucoses are rapidly trimmed by ER glucosidases I and II. Polypeptides exposing mono-glucosylated intermediates of N-glycan trimming associate with the ER lectins calnexin (Cnx) and calreticulin (Crt).The opposing actions of glucosidase II that trim the innermost glucose residue (thereby releasing the newly synthesized polypeptide from Cnx/Crt) and of UDP-glucose-glycoprotein glucosyltransferase that adds back one glucose to non-native conformers sending them back to Cnx/Crt, drive the so-called Cnx cycle (1, 2). For folding-incompetent and terminally misfolded glycopolypeptides, termination of unproductive folding attempts coincides with their definitive release from the Cnx cycle and deviation into the ERAD machinery. Interruption of unproductive folding attempts is a crucial step of ER quality control because it prevents clogging of the ER chaperone system.Emerging evidence underscores the importance of a tightly controlled extraction of folding-incompetent glycopolypeptides from the Cnx cycle to promote their degradation. Extraction is regulated by the ER ␣-mannosidase I (4) and by EDEM (ER degradation enhancing ␣-mannosidase-like protein (5)), an enzymatically inactive mannosidase-like protein. The ER ␣-mannosidase I cleaves one (6) or more (7) mannose residues...

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Section: Xbp1supporting

confidence: 75%

EDEM Contributes to Maintenance of Protein Folding Efficiency and Secretory Capacity

Eriksson¹,

Vago

Calanca³

et al. 2004

Journal of Biological Chemistry

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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

318

292

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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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“…ER-associated degradation involves the dislocation of selected substrates from the ER to the cytosol for proteolysis via the ubiquitin-proteasome system. This process is mediated by ER lumenal proteins Yos9p and EDEM, which interface directly with sugar moieties on target proteins (57)(58)(59) and by a ubiquitin ligase complex composed of the integral ER membrane proteins Hrd1p and Hrd3p (60,61). Hrd1p contains a NH 2 -terminal, multispanning membrane anchor and a COOH-terminal cytosolic domain, which contains a RING-H2 motif homologous to several characterized ubiquitin ligases.…”

Section: The Upr Maintains Cellular Homeostasis During Er Stressmentioning

confidence: 99%

The Unfolded Protein Response: A Novel Component of the Hypoxic Stress Response in Tumors

Feldman

Chauhan

Koong

2005

Molecular Cancer Research

278

222

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Hypoxia is a physiologically important endoplasmic reticulum (ER) stress that is present in all solid tumors. Numerous clinical studies have shown that tumor hypoxia predicts for decreased local control, increased distant metastases, and decreased overall survival in a variety of human tumors. Hypoxia selects for tumors with an increased malignant phenotype and increases the metastatic potential of tumor cells. Tumor cells respond to hypoxia and ER stress through the activation of the unfolded protein response (UPR). The UPR is an adaptive response to increase cell survival during ER stress. XBP-1 is a critical transcriptional regulator of this process and is required for tumor growth. Pancreatic ER kinase (PKR-like ER kinase) regulates the translational branch of the UPR and is also important in the growth of tumors. Although the exact mechanism has yet to be elucidated, recent data suggest that the UPR affects tumor growth through protection from apoptosis and may influence angiogenic signaling pathways. Targeting various components of the UPR is a promising therapeutic strategy. Understanding the relationship between hypoxia, the UPR, and tumor growth is crucial to improving current cancer therapies. (Mol Cancer Res 2005;3(11):597 -605)

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EDEM As an Acceptor of Terminally Misfolded Glycoproteins Released from Calnexin

Cited by 422 publications

References 25 publications

EDEM Contributes to Maintenance of Protein Folding Efficiency and Secretory Capacity

EDEM Contributes to Maintenance of Protein Folding Efficiency and Secretory Capacity

Protein Folding and Quality Control in the ER

The Unfolded Protein Response: A Novel Component of the Hypoxic Stress Response in Tumors

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