title: A new autophagy-related checkpoint in the degradation of an ERAD-M target.
abstract: The endoplasmic reticulum (ER) harbors elaborate quality control mechanisms to ensure proper folding and post-translational modifications of polypeptides targeted to this organelle. Once an aberrant protein is detected, it is dislocated from the ER and routed to the proteasome for destruction. Autophagy has been recently implicated in the elevation of the ER stress response; however, the involvement of this pathway in selective removal of ER-associated degradation (ERAD) substrates has not been demonstrated. In the present study, we show that an ER membrane lesion, associated with the accumulation of the yeast ERAD-M substrate 6Myc-Hmg2p elicits the recruitment of Atg8 and elements of the cytosol to vacuole targeting (CVT) to the membrane, leading to attenuation in the degradation process. Deletion of peptide:N-glycanase (PNG1) stabilizes this association, a process accompanied by slowdown of 6Myc-Hmg2p degradation. Truncation of the unstructured C-terminal 23 amino acids of 6Myc-Hmg2p rendered its degradation PNG1-independent and allowed its partial delivery to the vacuole in an autophagy-dependent manner. These findings demonstrate a new conduit for the selective vacuolar/lysosomal removal of ERAD misfolded proteins by an autophagy-related machinery acting concomitantly with the proteasome.
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Edith
authors.initials: E
authors.lastname: Kario
authors.forename: Nira
authors.initials: N
authors.lastname: Amar
authors.forename: Zvulun
authors.initials: Z
authors.lastname: Elazar
authors.forename: Ami
authors.initials: A
authors.lastname: Navon
mesh_terms: D001343:Autophagy / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D029701:Saccharomyces cerevisiae Proteins; C468820:PNG1 protein, S cerevisiae; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase