title: A novel quality control compartment derived from the endoplasmic reticulum.
abstract: Degradation of proteins that, because of improper or suboptimal processing, are retained in the endoplasmic reticulum (ER) involves retrotranslocation to reach the cytosolic ubiquitin-proteasome machinery. We found that substrates of this pathway, the precursor of human asialoglycoprotein receptor H2a and free heavy chains of murine class I major histocompatibility complex (MHC), accumulate in a novel preGolgi compartment that is adjacent to but not overlapping with the centrosome, the Golgi complex, and the ER-to-Golgi intermediate compartment (ERGIC). On its way to degradation, H2a associated increasingly after synthesis with the ER translocon Sec61. Nevertheless, it remained in the secretory pathway upon proteasomal inhibition, suggesting that its retrotranslocation must be tightly coupled to the degradation process. In the presence of proteasomal inhibitors, the ER chaperones calreticulin and calnexin, but not BiP, PDI, or glycoprotein glucosyltransferase, concentrate in the subcellular region of the novel compartment. The "quality control" compartment is possibly a subcompartment of the ER. It depends on microtubules but is insensitive to brefeldin A. We discuss the possibility that it is also the site for concentration and retrotranslocation of proteins that, like the mutant cystic fibrosis transmembrane conductance regulator, are transported to the cytosol, where they form large aggregates, the "aggresomes."
authors.affiliation: Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel, 69978.
authors.forename: S
authors.initials: S
authors.lastname: Kamhi-Nesher
authors.forename: M
authors.initials: M
authors.lastname: Shenkman
authors.forename: S
authors.initials: S
authors.lastname: Tolchinsky
authors.forename: S V
authors.initials: SV
authors.lastname: Fromm
authors.forename: R
authors.initials: R
authors.lastname: Ehrlich
authors.forename: G Z
authors.initials: GZ
authors.lastname: Lederkremer
mesh_terms: D016475:3T3 Cells; D000818:Animals; D020126:Brefeldin A / Q000494:pharmacology; D016466:CHO Cells; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D037281:Calnexin; D037282:Calreticulin; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000502:physiology*; D005805:Genes, MHC Class I; D006023:Glycoproteins / Q000378:metabolism; D006056:Golgi Apparatus; D006657:Histones / Q000378:metabolism; D015151:Immunoblotting; D051379:Mice; D008856:Microscopy, Fluorescence; D009097:Multienzyme Complexes / Q000378:metabolism; D051938:Munc18 Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017830:Octoxynol / Q000494:pharmacology; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D012261:Ribonucleoproteins / Q000737:chemistry / Q000378:metabolism; D013347:Subcellular Fractions; D013997:Time Factors; D014357:Trypsin / Q000494:pharmacology; D014452:Ubiquitins / Q000378:metabolism; D033921:Vesicular Transport Proteins
chemical_list: D002135:Calcium-Binding Proteins; D037282:Calreticulin; D003902:Detergents; D006023:Glycoproteins; D006657:Histones; D009097:Multienzyme Complexes; D051938:Munc18 Proteins; D009419:Nerve Tissue Proteins; D012261:Ribonucleoproteins; D014452:Ubiquitins; D033921:Vesicular Transport Proteins; C021645:chromatin conjugate protein A24; D037281:Calnexin; D020126:Brefeldin A; D017830:Octoxynol; D014357:Trypsin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex