Dissecting glycoprotein quality control in the secretory pathway

Cabral, Christopher M.; Liu, Yan; Sifers, Richard N.

doi:10.1016/s0968-0004(01)01942-9

Cited by 209 publications

(141 citation statements)

References 44 publications

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“…In fact, aberrant protein conformational rearrangement is the underlying etiologic agent of many genetic disorders. In the early exocytic pathway, secretory and membrane proteins unable to acquire native structure after biosynthesis are eliminated by a collection of processes designated ''endoplasmic reticulumassociated degradation'' (ERAD) (1)(2)(3)(4)(5)(6)(7)(8). Prominent molecular events currently under intense investigation include the retrograde translocation of substrates into the cytosol via the Sec61p channel, conjugation with ubiquitin, and subsequent degradation by the multicatalytic 26S proteasome (for reviews, see refs.…”

mentioning

confidence: 99%

Elucidation of the molecular logic by which misfolded α1-antitrypsin is preferentially selected for degradation

Wang

Swulius²,

Moremen³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

157

154

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The exocytic pathway provides a physical route through which newly synthesized secretory and membrane proteins are deployed to the eukaryote cell surface. For newly synthesized ␣1-antitrypsin (AAT), the modification of its asparagine-linked oligosaccharides by a slow-acting mannosidase partitions the misfolded monomer into the proteasomal degradation pathway. Herein, we asked whether, and how, modification by endoplasmic reticulum mannosidase I (ERManI) contributes to the preferential selection of the misfolded AAT monomer for proteasomal degradation. Transiently expressed mutant and WT AAT variants underwent rapid destabilization in response to an artificially elevated ERManI concentration in the murine hepatoma cell line, Hepa1a. Based on the mannosidase-and lactacystin-sensitive properties of intracellular turnover, a stochastic model is proposed in which the delayed onset of the glycan modification, relative to the duration of nonnative protein structure, coordinates the preferential degradation of the misfolded monomer and spares the native molecule from destruction. Newly synthesized endogenous transferrin underwent degradation in response to an elevated concentration of ERManI, whereas the nonglycosylated secretory glycoprotein albumin was not affected. Taken together, these findings indicate that efficient conformational maturation might function as the initial quality control standard for a broad population of glycoproteins.

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mentioning

confidence: 99%

Elucidation of the molecular logic by which misfolded α1-antitrypsin is preferentially selected for degradation

Wang

Swulius²,

Moremen³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

157

154

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“…Mannose trimming may therefore eventually lead to active extraction of folding incompetent glycoproteins from the folding attempts phase in the Cnx cycle (10 -17). Consistently, selective inhibition of ER ␣-mannosidase I with the alkaloid kifunensine (4,18) prevents hydrolysis of the Man9 structure (7), retards release of terminally misfolded glycoproteins from the Cnx cycle (19) and delays their degradation (reviewed in (11)). These findings are all in keeping with a mannose-timer model first proposed by Helenius (20) and refined in the last decade to include the kifunensine-sensitive ER ␣-mannosidase I as an essential factor determining the fate of glycoproteins with defective folding (1,2,4,21).…”

mentioning

confidence: 99%

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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“…On the other hand, TPβ, but not TPα, is subject to both tonic and agonist-induced internalization (10,11). Asparagine (N)-linked glycosylation is a major co-translational modification which occurs in the highly specialised environment of the endoplasmic reticulum and the golgi apparatus, and involves the initial transient interaction of specific lectin like chaperones, such as calnexin and its soluble homologue calreticulin (12), as well with co-chaperones which aid in protein folding and trafficking (13,14). In general, N-linked glycosylation is believed to play a major role in protein folding, maintaining the protein's correct conformation, aiding in intracellular trafficking, protein stability and in the cell surface expression of many glycoproteins (14)(15)(16)(17)(18).…”

Section: Discussionmentioning

confidence: 99%

The role of N-linked glycosylation in determining the surface expression, G protein interaction and effector coupling of the alpha (α) isoform of the human thromboxane A2 receptor

Kelley

Kinsella

2003

Biochimica et Biophysica Acta (BBA) - General Subjects

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Publication information Publisher's statementThis is the author's version of a work that was accepted for publication in Biochimica et Biophysica Acta. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Biochimica et Biophysica Acta

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Dissecting glycoprotein quality control in the secretory pathway

Cited by 209 publications

References 44 publications

Elucidation of the molecular logic by which misfolded α1-antitrypsin is preferentially selected for degradation

Elucidation of the molecular logic by which misfolded α1-antitrypsin is preferentially selected for degradation

EDEM Contributes to Maintenance of Protein Folding Efficiency and Secretory Capacity

The role of N-linked glycosylation in determining the surface expression, G protein interaction and effector coupling of the alpha (α) isoform of the human thromboxane A2 receptor

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