Mechanism and components of endoplasmic reticulum-associated degradation

Abstract

The folding of secretory and membrane proteins takes place in the endoplasmic reticulum (ER). The quality of the proteins folded in the ER is carefully monitored by an ER quality control mechanism that allows only correctly folded proteins to be transported to their final destination, and misfolded or unassembled proteins to be retained in the ER and subsequently degraded in a process termed 'ER-associated degradation' (ERAD). The ERAD pathway is conserved from yeast to mammals, and plays an essential role in the maintenance of ER homeostasis, as well as in the prevention of various diseases that arise from the accumulation of aberrant proteins in the ER. In the ERAD pathway, molecular chaperones and lectin-like proteins are involved in the identification of misfolded proteins, ER-resident reductases cleave disulfide bonds in these proteins to facilitate retrograde transport to the cytosol and AAA(+) adenosine triphosphatase withdraws them from the retrotranslocation channel to the cytosol where they are degraded by the ubiquitin/proteasome system. The possible mechanisms that underlie ERAD and the various factors involved in this process are discussed in this article.

The virulence of the opportunistic fungal pathogenAspergillus fumigatusrequires cooperation between the endoplasmic reticulum-associated degradation pathway (ERAD) and the unfolded protein response (UPR)

“…13 The purpose of this study was to determine the extent to which A. fumigatus also relies upon ERAD, a related pathway that works in conjunction with the UPR to maintain protein quality control in the ER. 10 The loss of the ERAD protein DerA had no detectable effect on the growth of the fungus, even under conditions of severe ER stress, similar to what has been described for the corresponding mutant in S. cerevisiae. 23 The ability of the ΔderA mutant to grow normally in the presence of ER stress contrasts the ΔhacA mutant, which is unable to survive when ER stress levels are high.…”

“…8,9 Two of the major pathways responsible for mitigating the ensuing stress are the unfolded protein response (UPR) 7 and ER-associated degradation (ERAD). 10 The UPR restores ER homeostasis by increasing the expression of proteins involved in protein folding and secretion. The pathway is triggered by the ER-membrane protein Ire1, which constitutes the major sensor of the fungal UPR.…”

Protein Folding and Quality Control in the ER

“…Our laboratory recently identified ERdj5 as an EDEM1-binding protein that can accelerate ERAD by reducing the incorrect formation of disulfide bonds in misfolded glycoproteins (Hoseki et al 2010). Based on its crystal structure, ERdj5 contains a J-domain and six tandem thioredoxin domains, two of which do not contain redox active CXXC motif (Hagiwara et al 2011).…”

The endoplasmic reticulum-associated degradation is necessary for plant salt tolerance

“…Similar to the general ubiquitination/degradation systems, it requires ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), ubiquitin ligase (E3), and 26S proteasome, as well as other associated proteins [5]. Because the process occurs in the ER, there are specific complexes involved, including at least some specific E2s and E3 and other associated proteins [6]. It is known that there are two different ERAD complexes in yeast, the HRD1/HRD3 complex and the DOA10 complex.…”