Lectins of the Emp47/ERGIC-53 family target misfolded O-mannosylated ER proteins to ER-associated degradation.

O-mannosylation of misfolded endoplasmic reticulum (ER) proteins in Saccharomyces cerevisiae by the bifunctional O-mannosyltransferase complex Pbn1-Gpi14 generates signals for ER-associated degradation (ERAD), but how these signals are recognized remains unknown. To address this question, we identify the binding partners of Pbn1 and find that the ER lectins Emp47 (ERGIC-53 in mammals) and Emp46 are among the strongest interactors. Simultaneous deletion of Emp46 and Emp47, but not of the lectin Yos9, impairs ERAD of an O-mannosylated, N-glycan-deficient CPY∗ variant. ERAD is restored by plasmid-expressed Emp47 or Emp46, but not by an Emp47 mutant lacking its carbohydrate-recognition domain (CRD). Furthermore, Emp47 interacts physically with the Hrd1 complex, suggesting that lectins of the Emp47/ERGIC-53 family recognize O-mannosylated misfolded proteins and target them for ERAD.