Abstract
Malectin is a conserved, endoplasmic reticulum (ER)-resident lectin that recognizes high mannose oligosaccharides displaying terminal glucose residues. Here we show that Malectin is an ER stress-induced protein that selectively associates with glycopolypeptides without affecting their entry and their retention in the Calnexin chaperone system. Analysis of the obligate Calnexin client influenza virus hemagglutinin (HA) revealed that Calnexin and Malectin associated with different timing to different HA conformers and that Malectin associated with misfolded HA. Analysis of the facultative Calnexin clients NHK and α1-antitrypsin (α1AT) revealed that induction of Malectin expression to simulate conditions of ER stress resulted in persistent association between the ER lectin and the model cargo glycoproteins, interfered with processing of cargo-linked oligosaccharides and reduced cargo secretion. We propose that Malectin intervention is activated upon ER stress to inhibit secretion of defective gene products that might be generated under conditions of aberrant functioning of the ER quality control machinery.
Highlights
In Eukarya, pre-assembled glucose3-mannose9-N-acetylglucosamine2- oligosaccharides (Fig. 1A) are transferred from a lipid donor in the endoplasmic reticulum (ER) membrane onto Asn-X-Ser/Thr sequons of nascent polypeptide chains emerging in the ER lumen
A novel ER lectin Malectin is a novel sugar binding, ER-resident protein highly conserved in Metazoa
Amongst lipid-linked high mannose oligosaccharides, Malectin shows a strong preference for glucose2-mannose7-N-acetylglucosamine1
Summary
In Eukarya, pre-assembled glucose3-mannose9-N-acetylglucosamine2- oligosaccharides (Fig. 1A) are transferred from a lipid donor in the ER membrane onto Asn-X-Ser/Thr sequons of nascent polypeptide chains emerging in the ER lumen. The translocon-associated a-glucosidase I removes the outermost glucose residue as soon as the oligosaccharide is covalently attached to the polypeptide chain emerging in the ER lumen. After, the soluble a-glucosidase II removes the second glucose This generates a mono-glucosylated oligosaccharide that recruits the lectin chaperones Calnexin and Calreticulin as well as the oxidoreductase ERp57 [3,4]. The co-translational association of nascent glycopolypeptides with Calnexin and Calreticulin [6,7,8] shows that generation of the mono-glucosylated intermediate of the oligosaccharide processing might occur in a matter of few seconds. The removal of up to 4 terminal mannose residues by the ER mannosidase I and by EDEM proteins eventually interrupts unproductive retention in the folding environment and directs terminally misfolded polypeptides to dislocons at the ER membrane. Dislocons contain adaptor proteins and membrane-embedded E3 ubiquitin ligases that regulate substrate retro-translocation across the ER membrane for proteasomal degradation [10,11,12]
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