Malectin Participates in a Backup Glycoprotein Quality Control Pathway in the Mammalian ER

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.

Protein Folding in the Endoplasmic Reticulum

“…Malectin was found to associate with endogenous aquaporin-2 in a large-scale proteomics study (Barile et al 2005). However, recent studies suggest that malectin binds aberrant substrates in the ER (Chen et al 2011;Galli et al 2011). This raises the question if malectin acts early in the maturation process, how can it already distinguish between native and aberrant proteins?…”

Malectin Forms a Complex with Ribophorin I for Enhanced Association with Misfolded Glycoproteins

“…Because malectin, a novel ER-resident protein, was first reported by the Xenopus laevis proteomic study, its selective binding to di-glucosylated high mannose-type N-glycans has led to much speculation regarding its function (12,13). By analogy with the mono-glucosylated N-glycan-binding lectins, CNX and CRT, which play an essential role in the folding of glycoproteins, malectin is also suggested to be involved in the quality control of glycoproteins in the ER.…”

“…By analogy with the mono-glucosylated N-glycan-binding lectins, CNX and CRT, which play an essential role in the folding of glycoproteins, malectin is also suggested to be involved in the quality control of glycoproteins in the ER. In fact, Galli et al (13) recently showed that malectin associates with newly synthesized glycoproteins, especially those with misfolded conformations, and subsequently interferes with their secretion. These results were confirmed by this study, which showed that malectin preferentially co-precipitated with misfolded AT NHK but not with wild-type AT (Fig.…”

“…Indeed, we and others demonstrated that malectin was induced under conditions of ER stress and is preferentially associated with foldingdefective glycoproteins (13,14). However, the molecular mechanisms by which malectin preferentially associates with misfolded glycoproteins are still not clear.…”

Cell Biology of the Endoplasmic Reticulum and the Golgi Apparatus through Proteomics

“…Briefly, newly synthesized N-linked glycoproteins are glycosylated with 14 sugars donated from a dolichol-linked lipid via oligosaccharyl transferase (Das and Heath 1980). Following the sequential removal of the terminal glucose by glucosidase I (Hettkamp et al 1984;Bause et al 1989), the glycoprotein may then be recognized by the protein malectin (Schallus et al 2008;Chen et al 2011;Galli et al 2011), potentially for presentation to glucosidase II for removal of the second glucose residue (Burns and Touster 1982;Reitman et al 1982;Pelletier et al 2000). The resulting mono-glucosylated glycoprotein is then a client for association with calnexin or calreticulin (Hammond et al 1994;Zapun et al 1997;Schrag et al 2003).…”