ERAD and ERAD tuning: disposal of cargo and of ERAD regulators from the mammalian ER

Abstract

The endoplasmic reticulum (ER) is the site of maturation for secretory and membrane proteins in eukaryotic cells. Unsuccessful folding attempts are eventually interrupted and most folding-defective polypeptides are dislocated across the ER membrane and degraded by cytosolic proteasomes in a complex series of events collectively defined as ER-associated degradation (ERAD). Uncontrolled ERAD activity might prematurely interrupt ongoing folding programs. At steady state, this is prevented by ERAD tuning, that is, the removal of select ERAD regulators from the ER and their degradation by proteasomes and by endo-lysosomal proteases. In Coronaviruses infected cells, the formation of LC3-I coated vesicles containing ERAD regulators cleared from the ER lumen is co-opted to anchor viral replication and transcription complexes to ER-derived membranes.

Protein Folding and Quality Control in the ER

“…At steady state, short-living ERAD components like EDEM1 and OS-9 appeared to be engulfed in these buds in a COPII-independent manner and degraded without the attachment of nonlipidated LC3. This turnover of ERAD factors, known as ERAD tuning, maintains an extra capacity of ERAD factors at steady state by EDEMosome-linked degradation (Bernasconi and Molinari 2011). It is hypothesized that this makes it possible for the ER to respond quickly to sudden changes without waiting for transcriptional UPR responses.…”

The E2 Ubiquitin-conjugating Enzyme UBE2J1 Is Required for Spermiogenesis in Mice

“…The amount of such components, perhaps not surprisingly, may be controlled dynamically (29,30), according to the immediate needs of the cell. In vivo ablation of Ube2j1 Ϫ/Ϫ may thus reveal the existence of a feedback loop in which activation of Ube2j1 attenuates the levels of OS9, EDEM1, and SEL1L.…”

CD4 and BST-2/Tetherin Proteins Retro-translocate from Endoplasmic Reticulum to Cytosol as Partially Folded and Multimeric Molecules

“…Although ERAD has been widely studied both in yeast and mammalian cells (3,10), a comprehensive picture of how the retro-translocation step works is still missing, particularly in relation to the requirements of the substrate and the structure of the molecular complex that actually drives dislocation. Here we report on the mechanism of retro-translocation of two widely studied proteins, CD4 and BST-2/Tetherin, using a novel technique to detect retro-translocation of defined proteins, based on the specific biotinylation in living cells only of molecules that from the ER reach the cytosolic compartment (11).…”