NEW EMBO MEMBER'S REVIEW: For whom the bell tolls: protein quality control of the endoplasmic reticulum and the ubiquitin-proteasome connection

Abstract

The surveillance of the structural fidelity of the proteome is of utmost importance to all cells. The endoplasmic reticulum (ER) is the organelle responsible for proper folding and delivery of proteins to the secretory pathway. It contains a sophisticated protein proofreading and elimination mechanism. Failure of this machinery leads to disease and, finally, to cell death. Elimination of misfolded proteins requires retrograde transport across the ER membrane and depends on the central cytoplasmic proteolytic machinery involved in cellular regulation: the ubiquitin–proteasome system. The basics of this process as well as recent advances in the field are reviewed.

Characterization of anERADGene asVPS30/ATG6Reveals Two Alternative and Functionally Distinct Protein Quality Control Pathways: One for Soluble Z Variant of Human α-1 Proteinase Inhibitor (A1PiZ) and Another for Aggregates of A1PiZ

“…Although two cellular sites of proteolysis are known, the lysosome/vacuole and cytoplasmic 26S proteasome, the recognition of aberrant proteins and mechanisms for delivery to these sites are still being defined. Endoplasmic reticulum-associated degradation (ERAD) is a protein quality control process in which aberrant or misassembled proteins in the secretory pathway are identified and removed (reviewed in Hampton, 2002;Tsai et al, 2002;Kostova and Wolf, 2003;McCracken and Brodsky, 2003). After entering the endoplasmic reticulum (ER), a nascent protein that fails to fold or assemble properly can be "recognized" by the ER quality control machinery, retained within the ER, and then retrotranslocated to the cytoplasm where it is degraded by the proteasome.…”

Decreased ER-associated degradation of α-TCR induced by Grp78 depletion with the SubAB cytotoxin

“…After co-translational insertion into the ER, new proteins undergo folding, assembly, and posttranslational modifications which are scrutinized by a rigorous quality control mechanism (Ellgaard and Helenius, 2003). Misfolded proteins which fail to refold properly are retrotranslocated to the cytosol where they undergo degradation mediated by the ubiquitin-and proteasome system (UPS), a process known as ER-associated degradation (ERAD) (Ahner and Brodsky, 2004;Ellgaard and Helenius, 2003;Kostova and Wolf, 2003;Sitia and Braakman, 2003;Tsai et al, 2002). An increase in protein misfolding within the ER leads to an integrated cellular response, which involves translational attenuation, decreasing the input of new proteins, followed by a transcriptional reaction known as unfolded protein response (UPR) (Hampton, 2003;Harding et al, 2002;Ma and Hendershot, 2002;Shen et al, 2004).…”

Inositol Deacylation by Bst1p Is Required for the Quality Control of Glycosylphosphatidylinositol-anchored Proteins

“…Before exiting from the ER, proteins are monitored by a quality control system that ensures correct folding. Misfolded proteins that fail to pass the quality control checkpoint are transported back to the cytosol and degraded by an ER-associated degradation (ERAD) mechanism that involves the ubiquitinproteasome pathway (Kopito, 1997;Kostova and Wolf, 2003). N-linked oligosaccharide, one of the major posttranslational modifications in the ER, is trimmed and processed by glucosidase I, glucosidase II, and mannosidase I (Jakob et al, 1998;Helenius and Aebi, 2001).…”