A Shared Endoplasmic Reticulum-associated Degradation Pathway Involving the EDEM1 Protein for Glycosylated and Nonglycosylated Proteins

• Published in: The Journal of biological chemistry Vol. 288; no. 4; pp. 2167 - 2178
• Main Authors: Shenkman, Marina, Groisman, Bella, Ron, Efrat, Avezov, Edward, Hendershot, Linda M., Lederkremer, Gerardo Z.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.01.2013; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Chaperone Chaperonin; Chaperonins - chemistry; Cytosol - metabolism; EDEM1; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum-Associated Degradation; ER-associated Degradation; Gene Expression Regulation; Glycosylation; HEK293 Cells; HRD1; Humans; Igκ Light Chain; Immunoglobulin kappa-Chains - chemistry; Lectin; Lectins - chemistry; Mannosidases - chemistry; Membrane Proteins - metabolism; Mice; NIH 3T3 Cells; Polysaccharides - chemistry; Protein Degradation; Protein Denaturation; Protein Folding; Protein Misfolding; Protein Synthesis and Degradation; Lectin; Protein Misfolding; Chaperone Chaperonin; EDEM1; HRD1; Protein Degradation; Igκ Light Chain; ER-associated Degradation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.438275

Studies of misfolded protein targeting to endoplasmic reticulum-associated degradation (ERAD) have largely focused on glycoproteins, which include the bulk of the secretory proteins. Mechanisms of targeting of nonglycosylated proteins are less clear. Here, we studied three nonglycosylated proteins and analyzed their use of known glycoprotein quality control and ERAD components. Similar to an established glycosylated ERAD substrate, the uncleaved precursor of asialoglycoprotein receptor H2a, its nonglycosylated mutant, makes use of calnexin, EDEM1, and HRD1, but only glycosylated H2a is a substrate for the cytosolic SCFFbs2 E3 ubiquitin ligase with lectin activity. Two nonglycosylated BiP substrates, NS-1κ light chain and truncated Igγ heavy chain, interact with the ERAD complex lectins OS-9 and XTP3-B and require EDEM1 for degradation. EDEM1 associates through a region outside of its mannosidase-like domain with the nonglycosylated proteins. Similar to glycosylated substrates, proteasomal inhibition induced accumulation of the nonglycosylated proteins and ERAD machinery in the endoplasmic reticulum-derived quality control compartment. Our results suggest a shared ERAD pathway for glycosylated and nonglycosylated proteins composed of luminal lectin machinery components also capable of protein-protein interactions. Background:N-Glycan processing and interactions with lectins regulate the quality control and endoplasmic reticulum-associated degradation (ERAD) of glycoproteins. Results: Most of the same machinery targets nonglycosylated misfolded proteins. Conclusion: They share some membrane and luminal ERAD machinery but not all cytosolic components. Significance: ER glycan-interacting proteins must possess a dual specificity for glycan structure and for exposed misfolded polypeptide domains.