The role of UDP-Glc:glycoprotein glucosyltransferase 1 in the maturation of an obligate substrate prosaposin

Pearse, Bradley R.; Tamura, Taku; Sunryd, Johan C.; Grabowski, Gregory A.; Kaufman, Randal J.; Hebert, Daniel N.

doi:10.1083/jcb.200912105

Cited by 39 publications

(30 citation statements)

References 71 publications

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“…On the other hand, we can no rule out that a protein of the PDI family could be trapped in these complexes. A novel endogenous UGGT substrate named prosaposin has been recently identified in mammalian cells [36]. Similarly to our observation, in uggt −/− cells prosaposin secretion is severely impaired and the protein localizes to aggresome-like inclusions.…”

Section: Discussionsupporting

confidence: 87%

Functional cooperation between BiP and calreticulin in the folding maturation of a glycoprotein in Trypanosoma cruzi

Labriola

Giraldo

Parodi

et al. 2011

Molecular and Biochemical Parasitology

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Proteins may adopt diverse conformations during their folding in vivo, ranging from extended chains when they emerge from the ribosome to compact intermediates near the end of the folding process. Accordingly, a variety of chaperones and folding assisting enzymes have evolved to deal with this diversity. Chaperone selection by a particular substrate depends on the structural features of its folding intermediates. In addition, this process may be modulated by competitive effects between chaperones. Here we address this issue by using TcrCATL as model substrate. TcrCATL is an abundant Trypanosoma cruzi lysosomal protease and it was the first identified endogenous UDP-Glc:glycoprotein glucosyltransferase (UGGT) substrate. We found that TcrCATL associated sequentially with BiP and calreticulin (CRT) during its folding process. Early, extended conformations were bound to BiP, while more advanced and compact folding intermediates associated to CRT. The interaction between TcrCATL and CRT was impeded by deletion of the UGGT-encoding gene but, similarly to what was observed in wild type cells, in mutant cells TcrCATL associated to BiP only when displaying extended conformations. The absence of TcrCATL-CRT interactions in UGGT null cells resulted in a drastic reduction of TcrCATL folding efficiency and triggered the aggregation of TcrCATL through intermolecular disulfide bonds. These observations show that BiP and CRT activities complement each other to supervise a complete and efficient TcrCATL folding process. The present report provides further evidence on the early evolutionary acquisition of the basic tenets of the N-glycan dependent quality control mechanism of glycoprotein folding.

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Section: Discussionsupporting

confidence: 87%

Functional cooperation between BiP and calreticulin in the folding maturation of a glycoprotein in Trypanosoma cruzi

Labriola

Giraldo

Parodi

et al. 2011

Molecular and Biochemical Parasitology

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“…Similar delays have been observed for a number of glycoproteins, including influenza virus hemagglutinin, both for glucose trimming (33) and substrate release from CNX (13). The reason for this delay is poorly understood.…”

Section: Discussionmentioning

confidence: 66%

A role for UDP-glucose glycoprotein glucosyltransferase in expression and quality control of MHC class I molecules

Zhang

Wearsch

Zhu

et al. 2011

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

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UDP-glucose:glycoprotein glucosyltransferase 1 (UGT1) serves as a folding sensor in the calnexin/calreticulin glycoprotein quality control cycle. UGT1 recognizes disordered or hydrophobic patches near asparagine-linked nonglucosylated glycans in partially misfolded glycoproteins and reglucosylates them, returning folding intermediates to the cycle. In this study, we examine the contribution of the UGT1-regulated quality control mechanism to MHC I antigen presentation. Using UGT1-deficient mouse embryonic fibroblasts reconstituted or not with UGT1, we show that, although formation of the peptide loading complex is unaffected by the absence of UGT1, the surface level of MHC class I molecules is reduced, MHC class I maturation and assembly are delayed, and peptide selection is impaired. Most strikingly, we show using purified soluble components that UGT1 preferentially recognizes and reglucosylates MHC class I molecules associated with a suboptimal peptide. Our data suggest that, in addition to the extensively studied tapasin-mediated quality control mechanism, UGT1 adds a new level of control in the MHC class I antigen presentation pathway.antigen processing | chaperones M ajor histocompatibility complex (MHC) class I-mediated antigen presentation is critical for adaptive immune responses to intracellular pathogens. MHC class I assembly and peptide loading constitute a specialized case of glycoprotein folding, using general chaperones and enzymes involved in the endoplasmic reticulum (ER) quality control machinery as well as MHC class I-specific cofactors. Like other glycoproteins, MHC class I heavy chains (HCs) are modified during translocation by asparagine (N)-linked glycosylation with the glycan Glc 3 Man 9 GlcNAc 2 . After the first two glucose residues are trimmed by glucosidases I (GlsI) and II (GlsII), the monoglucosylated (Glc 1 Man 9 GlcNAc 2 ) glycan interacts with the lectin chaperone calnexin (CNX) for oxidative folding (1). The maturing HCs are partially stabilized by β 2 -microglobulin (β 2 m) association, and the HC/β 2 m dimers are recruited by the second lectin chaperone calreticulin (CRT) into the peptide loading complex (PLC) via their monoglucosylated glycans (2, 3). The PLC is composed of the HC/β 2 m dimer, CRT, the transporter associated with antigen processing (TAP), and a disulfide-linked tapasin-ERp57 conjugate (reviewed in ref. 4). It facilitates peptide loading onto MHC class I molecules and functions in quality control by retaining empty and suboptimally loaded MHC class I molecules in the ER.The glycosylation status of ER MHC class I molecules is highly regulated. Monoglucosylation is not detectable in free human MHC class I HCs (5), whereas PLC-associated HCs are virtually all monoglucosylated (3, 5). Inhibiting deglucosylation of the monoglucosylated glycan prolongs the interaction of MHC class I molecules with the PLC (3, 6), and, in vitro, GlsII can trim the monoglucosylated glycans of free HCs but not PLC-associated HCs (3). This suggests that only when MHC class I molecules dis...

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“…However, the sequential domain lysosomal protein prosaposin is an obligate substrate of UGT1 as it misfolds and is found in aggresome-like structures in its absence (118). Prosaposin is efficiently reglucosylated by UGT1 as demonstrated using a cell-based reglucosylation assay.…”

Section: Role Of Ugt1 As a Folding Sensormentioning

confidence: 99%

N-linked sugar-regulated protein folding and quality control in the ER

Tannous

Pisoni

Hebert

et al. 2015

Seminars in Cell & Developmental Biology

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218

192

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Asparagine-linked glycans (N-glycans) are displayed on the majority of proteins synthesized in the endoplasmic reticulum (ER). Removal of the outermost glucose residue recruits the lectin chaperone malectin possibly involved in a first triage of defective polypeptides. Removal of a second glucose promotes engagement of folding and quality control machineries built around the ER lectin chaperones calnexin (CNX) and calreticulin (CRT) and including oxidoreductases and peptidyl-prolyl isomerases. Deprivation of the last glucose residue dictates the release of N- glycosylated polypeptides from the lectin chaperones. Correctly folded proteins are authorized to leave the ER. Non-native polypeptides are recognized by the ER quality control key player UDP-glucose glycoprotein glucosyltransferase 1 (UGT1), re-glucosylated and re-addressed to the CNX/CRT chaperone binding cycle to provide additional opportunity for the protein to fold in the ER. Failure to attain the native structure determines the selection of the misfolded polypeptides for proteasome-mediated degradation.

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The role of UDP-Glc:glycoprotein glucosyltransferase 1 in the maturation of an obligate substrate prosaposin

Abstract: A natural substrate for UGT1 is confirmed, revealing how the enzyme functions in the calnexin chaperone system as a quality control step in protein folding.

Cited by 39 publications

References 71 publications

Functional cooperation between BiP and calreticulin in the folding maturation of a glycoprotein in Trypanosoma cruzi

Functional cooperation between BiP and calreticulin in the folding maturation of a glycoprotein in Trypanosoma cruzi

A role for UDP-glucose glycoprotein glucosyltransferase in expression and quality control of MHC class I molecules

N-linked sugar-regulated protein folding and quality control in the ER

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