Endoplasmic reticulum‐associated degradation of glycoproteins bearing Man5GlcNAc2 and Man9GlcNAc2 species in the MI8‐5 CHO cell line

Foulquier, François; Duvet, Sandrine; Klein, André; Mir, Anne-Marie; Chirat, Frédéric; Cacan, René

doi:10.1046/j.1432-1033.2003.03938.x

Cited by 28 publications

(12 citation statements)

References 28 publications

(34 reference statements)

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“…None of these structures expose Manα1,3Manβ1,4GlcNAc, terminally at the non-reducing end of the glycan branch. Perhaps this is not so striking, as glycoproteins bearing Man 5 GlcNAc 2 glycans are degraded preferentially [39]. The only isomer of oligomannose-6 encountered so far on uroplakins covers Manα1,3Manβ1,4GlcNAc with an extra α1,2-linked d -mannose [37], thus masking the epitope with high affinity for FimH [40].…”

Section: Introductionmentioning

confidence: 99%

Intervening with Urinary Tract Infections Using Anti-Adhesives Based on the Crystal Structure of the FimH–Oligomannose-3 Complex

et al. 2008

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Background Escherichia coli strains adhere to the normally sterile human uroepithelium using type 1 pili, that are long, hairy surface organelles exposing a mannose-binding FimH adhesin at the tip. A small percentage of adhered bacteria can successfully invade bladder cells, presumably via pathways mediated by the high-mannosylated uroplakin-Ia and α3β1 integrins found throughout the uroepithelium. Invaded bacteria replicate and mature into dense, biofilm-like inclusions in preparation of fluxing and of infection of neighbouring cells, being the major cause of the troublesome recurrent urinary tract infections.Methodology/Principal FindingsWe demonstrate that α-d-mannose based inhibitors of FimH not only block bacterial adhesion on uroepithelial cells but also antagonize invasion and biofilm formation. Heptyl α-d-mannose prevents binding of type 1-piliated E. coli to the human bladder cell line 5637 and reduces both adhesion and invasion of the UTI89 cystitis isolate instilled in mouse bladder via catheterization. Heptyl α-d-mannose also specifically inhibited biofilm formation at micromolar concentrations. The structural basis of the great inhibitory potential of alkyl and aryl α-d-mannosides was elucidated in the crystal structure of the FimH receptor-binding domain in complex with oligomannose-3. FimH interacts with Manα1,3Manβ1,4GlcNAcβ1,4GlcNAc in an extended binding site. The interactions along the α1,3 glycosidic bond and the first β1,4 linkage to the chitobiose unit are conserved with those of FimH with butyl α-d-mannose. The strong stacking of the central mannose with the aromatic ring of Tyr48 is congruent with the high affinity found for synthetic inhibitors in which this mannose is substituted for by an aromatic group.Conclusions/SignificanceThe potential of ligand-based design of antagonists of urinary tract infections is ruled by the structural mimicry of natural epitopes and extends into blocking of bacterial invasion, intracellular growth and capacity to fluxing and of recurrence of the infection.

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Section: Introductionmentioning

confidence: 99%

Intervening with Urinary Tract Infections Using Anti-Adhesives Based on the Crystal Structure of the FimH–Oligomannose-3 Complex

et al. 2008

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“…The former substrate has individual 1M residues coupled in various numbers to BSA, which are likely to interact with FimH via a single mannose interaction involving the monomannose-binding pocket on the top of the lectin domain. Mannose residues in the 3M substrate, bovine RNase B, are part of the high-mannose, type N-linked oligosaccharides, where about half are in the Man5GlcNAc2 configuration (14 (12). Not surprisingly, the majority of glycoproteins tested so far bind FimH exclusively or primarily in a 1M-specific manner (35).…”

Section: Discussionmentioning

confidence: 99%

Comparative Structure-Function Analysis of Mannose-Specific FimH Adhesins from Klebsiella pneumoniae and Escherichia coli

Stahlhut

Tchesnokova²,

Struve

et al. 2009

J Bacteriol

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FimH, the adhesive subunit of type 1 fimbriae expressed by many enterobacteria, mediates mannosesensitive binding to target host cells. At the same time, fine receptor-structural specificities of FimH from different species can be substantially different, affecting bacterial tissue tropism and, as a result, the role of the particular fimbriae in pathogenesis. In this study, we compared functional properties of the FimH proteins from Escherichia coli and Klebsiella pneumoniae, which are both 279 amino acids in length but differ by some ϳ15% of residues. We show that K. pneumoniae FimH is unable to mediate adhesion in a monomannose-specific manner via terminally exposed Man␣(1-2) residues in N-linked oligosaccharides, which are the structural basis of the tropism of E. coli FimH for uroepithelial cells. However, K. pneumoniae FimH can bind to the terminally exposed Man␣(1-3)Man␤(1-4)GlcNAc␤1 trisaccharide, though only in a shear-dependent manner, wherein the binding is marginal at low shear force but enhanced sevenfold under increased shear. A single mutation in the K. pneumoniae FimH, S62A, converts the mode of binding from shear dependent to shear independent. This mutation has occurred naturally in the course of endemic circulation of a nosocomial uropathogenic clone and is identical to a pathogenicity-adaptive mutation found in highly virulent uropathogenic strains of E. coli, in which it also eliminates the dependence of E. coli binding on shear. The sheardependent binding properties of the K. pneumoniae and E. coli FimH proteins are mediated via an allosteric catch bond mechanism. Thus, despite differences in FimH structure and fine receptor specificity, the sheardependent nature of FimH-mediated adhesion is highly conserved between bacterial species, supporting its remarkable physiological significance.

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“…Persistent ER retention of misfolded conformers elicits intervention of ER-resident mannosidases of the glycosyl hydrolase 47 family (48) comprising the ERManI, EDEM1, EDEM2, EDEM3. These directly or indirectly enhance removal of α1,2-bonded mannose residues (49)(50)(51)(52)(53)(54)(55)(56)(57) to extract misfolded polypeptides from the calnexin chaperone system (58) and to generate disposal signals decoded by mannose-binding ERAD lectins such as OS-9 and XTP3-B variants (50,51,(59)(60)(61)(62). The ERAD lectins, which are interchangeable in function at least for soluble ERAD substrates (ERAD-L S ) (63), shuttle misfolded polypeptides from the ER lumen to dislocation sites in the ER membrane ( Figure 2).…”

Section: The Presence Of N-linked Oligosaccharidesmentioning

confidence: 99%

Specificity and Regulation of the Endoplasmic Reticulum‐Associated Degradation Machinery

Merulla

Fasana

Soldà

et al. 2013

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The endoplasmic reticulum-associated degradation (ERAD) machinery selects native and misfolded polypeptides for dislocation across the ER membrane and proteasomal degradation. Regulated degradation of native proteins is an important aspect of cell physiology. For example, it contributes to the control of lipid biosynthesis, calcium homeostasis and ERAD capacity by setting the turnover rate of crucial regulators of these pathways. In contrast, degradation of native proteins has pathologic relevance when caused by viral or bacterial infections, or when it occurs as a consequence of dysregulated ERAD activity. The efficient disposal of misfolded proteins prevents toxic depositions and persistent sequestration of molecular chaperones that could induce cellular stress and perturb maintenance of cellular proteostasis. In the first section of this review, we survey the available literature on mechanisms of selection of native and non-native proteins for degradation from the ER and on how pathogens hijack them. In the second section, we highlight the mechanisms of ERAD activity adaptation to changes in the ER environment with a particular emphasis on the post-translational regulatory mechanisms collectively defined as ERAD tuning. The cellular proteome is mostly synthesized by cytosolic ribosomes to operate in the cytosol and, upon appropriate targeting, in various intracellular organelles or in the extracellular space. Cellular compartments where protein folding occurs [e.g. the cytosol, mitochondria, the endoplasmic reticulum (ER)] contain two classes of non-native polypeptides: (i) newly synthesized polypeptide chains that must be assisted by folding chaperones and enzymes to attain the native mono-or oligomeric structure; (ii) terminally misfolded conformers that must efficiently be degraded to prevent the formation of toxic deposits and the persistent sequestration of chaperones that could eventually inhibit the cellular protein folding capacity and elicit stress (1-3) ( Figure 1A). The distinction between the two classes of non-native chains, one to be preserved, the second to be cleared from the folding compartment, is not an easy task for the cellular quality control machineries. Selection for disposal might be a stochastic process: the longer the persistency of structural defects in the ER, the greater is the probability to be selected for destruction. Therefore, mutations that delay folding may channel the polypeptide into destructive pathways, even if they do not compromise the function of the mutated protein.In the ER, non-native, but also native proteins might be selected for degradation by components of the endoplasmic reticulum-associated degradation (ERAD) machinery that deliver them at dislocation sites embedded in the ER membrane. Dislocation sites consist of a multitude of luminal and membrane-bound specialized ER-resident proteins as well as a number of cytosolic factors insuring dislocation across the ER membrane, poly-ubiquitylation and disposal of ERAD substrates by 26S proteasomes (Specificity of...

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Endoplasmic reticulum‐associated degradation of glycoproteins bearing Man5GlcNAc2 and Man9GlcNAc2 species in the MI8‐5 CHO cell line

Cited by 28 publications

References 28 publications

Intervening with Urinary Tract Infections Using Anti-Adhesives Based on the Crystal Structure of the FimH–Oligomannose-3 Complex

Intervening with Urinary Tract Infections Using Anti-Adhesives Based on the Crystal Structure of the FimH–Oligomannose-3 Complex

Comparative Structure-Function Analysis of Mannose-Specific FimH Adhesins from Klebsiella pneumoniae and Escherichia coli

Specificity and Regulation of the Endoplasmic Reticulum‐Associated Degradation Machinery

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