SnapShot: ER-Associated Protein Degradation Pathways

Abstract

(A) Newly synthesized secretory and membrane proteins enter the ER through the Sec61 protein-conducting channel complex unfolded. Hsp70-related molecular chaperones (Kar2p) bind to nascent polypeptides in the ER lumen and to the cytosolic domains of membrane proteins (Hsp70, B). These factors assist in substrate folding and also assist in their disposal if they fail to fold. Mannose residues on misfolded glycoproteins are trimmed by the ER mannosidase Mns1p (E). Mannose trimming facilitates the recognition of misfolded glycoproteins by luminally oriented lectin factors Htm1p and Yos9p. (C, D, and F) At least two ER membrane-localized E3 ubiquitin ligases organize protein complexes that receive and process misfolded proteins. These complexes define three pathways that recognize lesions in the cytosolic (ERAD-C), transmembrane (ERAD-M), and luminal (ERAD-L) domains of substrates. Both ERAD-M and ERAD-L use the Hrd1 ubiquitin ligase but the luminal factor Yos9p is dispensable for ERAD-M. A Hrd1 complex lacking Yos9p has been observed suggesting dedicated complexes for all three pathways. As ubiquitina-tion and degradation occurs in the cytosol, luminal substrates must be retrotranslocated. The identity of the conduit remains unresolved in the ubiquitin-dependent pathways, but the Sec61 complex and Der1 family members have been implicated. (G) In the yeast ubiquitin-independent pathway, misfolded proα-factor in yeast exits via Sec61. Cdc48p/p97 and its cofactors Npl4p and Ufd1p provide the driving force for the extraction of ubiquitinated luminal and membrane substrates from the ER membrane. In association with the Cdc48p/p97 complex, the E4 enzyme Ufd2p remodels ubiquitin chains. The polyubiquitinated substrate is transferred to the Rad23p or Dsk2p complexes assisted through an association with Ufd2p (H). N-linked glycans are removed by Png1p. Finally, the substrate is targeted by this complex to the proteasome where it is degraded (I).