Basal autophagy is involved in the degradation of the ERAD component EDEM1

Fourn, Valérie Le; Gaplovská-Kyselá, Katarína; Guhl, Bruno; Santimaria, Roger; Zuber, Christian; Roth, Jürgen

doi:10.1007/s00018-009-9038-1

Cited by 39 publications

(61 citation statements)

References 57 publications

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“…In support of this, electron microscopy showed that EDEM1 is primarily localized in double-membrane buds that form outside canonical ER exit sites, known as EDEMosomes (Zuber et al 2007;Le Fourn et al 2009;Reggiori et al 2010). 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.…”

Section: Other Degradation Pathwaysmentioning

confidence: 88%

Protein Folding and Quality Control in the ER

Araki

Nagata

2011

Cold Spring Harbor Perspectives in Biology

326

285

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The endoplasmic reticulum (ER) uses an elaborate surveillance system called the ER quality control (ERQC) system. The ERQC facilitates folding and modification of secretory and membrane proteins and eliminates terminally misfolded polypeptides through ER-associated degradation (ERAD) or autophagic degradation. This mechanism of ER protein surveillance is closely linked to redox and calcium homeostasis in the ER, whose balance is presumed to be regulated by a specific cellular compartment. The potential to modulate proteostasis and metabolism with chemical compounds or targeted siRNAs may offer an ideal option for the treatment of disease.

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Section: Other Degradation Pathwaysmentioning

confidence: 88%

Protein Folding and Quality Control in the ER

Araki

Nagata

2011

Cold Spring Harbor Perspectives in Biology

326

285

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“…Second, EDEM1 migrated as a protein doublet by SDS-PAGE that appeared to be caused by heterogeneous glycosylation (30). Third, EDEM1 was shown to be turned over rapidly in some cell lines through autophagic or autophagic-like pathways (45,46). Fourth, EDEM1 localized to the ER and large vesicles that exit the ER in a COPII-independent manner (30,47).…”

Section: Discussionmentioning

confidence: 97%

“…2). As the halflife of EDEM1 is relatively short in a variety of cell lines (ϳ1 h) (45,46), this brought up the questions of whether both forms of EDEM1 are active? Do they work in different complexes and have different substrate specificities?…”

Section: Discussionmentioning

confidence: 99%

Characterization of Early EDEM1 Protein Maturation Events and Their Functional Implications

Tamura

Cormier

Hebert

2011

Journal of Biological Chemistry

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The endoplasmic reticulum (ER) quality control factor EDEM1 associates with a number of ER proteins and ER-associated degradation (ERAD) substrates; however, an understanding of its role in ERAD is unclear. The early maturation events for EDEM1 including signal sequence cleavage and glycosylation were analyzed, and their relationship to the function of EDEM1 was determined. EDEM1 has five N-linked glycosylation sites with the most C-terminal site recognized poorly cotranslationally, resulting in the accumulation of EDEM1 containing four or five glycans. The fifth site was modified post-translationally when bypassed cotranslationally. Signal sequence cleavage of EDEM1 was found to be a slow and inefficient process. Signal sequence cleavage produced a soluble form of EDEM1 that efficiently associated with the oxidoreductase ERdj5 and most effectively accelerated the turnover of a soluble ERAD substrate. In contrast, a type-II membrane form of EDEM1 was generated when the signal sequence was uncleaved, creating an N-terminal transmembrane segment. The membrane form of EDEM1 efficiently associated with the ER membrane protein SEL1L and accelerated the turnover of a membrane-associated ERAD substrate. Together, these results demonstrated that signal sequence cleavage functionally regulated the association of EDEM1-soluble and membrane-integrated isoforms with distinct ERAD machinery and substrates.The signal hypothesis states that proteins are targeted to the eukaryotic secretory pathway by hydrophobic signal sequences that are frequently positioned at the N terminus of the protein (1). These proteins are cotranslationally targeted and translocated across the endoplasmic reticulum (ER) 2 membrane where the vast majority of the maturation process occurs. Maturation events include signal sequence cleavage, protein folding, covalent modification, and assembly (2). The ER contains a number of factors that aid in these steps for secretory and membrane proteins. As protein maturation is an error-prone process, the ER also possesses a quality control process that monitors the successfulness of these steps (3, 4). Quality control factors dedicated to the evaluation and sorting of maturing proteins target defective proteins for destruction by the cytoplasmic proteasome after their dislocation through the ER membrane by a process termed ER-associated degradation (ERAD). Although many of the players involved in ER quality control have been uncovered over the past decade, there is still much to be learned about the mechanism of the quality control process.Signal sequences that target proteins to the ER generally consist of the first 20 -30 amino acids of a protein organized into three domains (5). Signal sequences start with a basic N-terminal domain (N-domain) followed by an extended hydrophobic domain (H-domain; ϳ7-13 amino acids in length) and a polar domain (C-domain) that contains low molecular weight amino acids near the cleavage site. Recent evidence indicates that signal sequences do not solely provide transient targetin...

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“…A recent study provided evidence that endogenous ER degradation-enhancing a mannosidase-like protein (EDEM1) in nonstressed cells reaches the cytosol and is degraded by basal autophagy. 69 The detailed signaling pathway for activation of the autophagy induced by ER stress awaits further analysis. Both autophagy and ER stress have been implicated in certain human diseases, such as Parkinson and Huntington diseases 70,71 and diabetes.…”

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confidence: 99%

The role of autophagy in endoplasmic reticulum stress-induced pancreatic β cell death

Yin

Wang

et al. 2012

Autophagy

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Shang-Ha Pan (2012) The role of autophagy in endoplasmic reticulum stress-induced pancreatic β cell death, Autophagy, 8:2,[158][159][160][161][162][163][164] DOI: 10.4161 Keywords: autophagy, endoplasmic reticulum stress, pancreatic beta cell, free fatty acid, glucagon like peptide-1In pancreatic b-cells, the endoplasmic reticulum (ER) is the crucial site for insulin biosynthesis, as this is where the proteinfolding machinery for secretory proteins is localized. Perturbations to ER function of the b-cell, such as those caused by high levels of free fatty acid and insulin resistance, can lead to an imbalance in protein homeostasis and ER stress, which has been recognized as an important mechanism for type 2 diabetes. Macroautophagy (hereafter referred to as autophagy) is activated as a novel signaling pathway in response to ER stress. In this review, we outline the mechanism of ER stress-mediated b-cell death and focus on the role of autophagy in ameliorating ER stress. The development of drugs to take advantage of the potential protective effect of autophagy in ER stress, such as glucagon like peptide-1, will be a promising avenue of investigation.

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Basal autophagy is involved in the degradation of the ERAD component EDEM1

Cited by 39 publications

References 57 publications

Protein Folding and Quality Control in the ER

Protein Folding and Quality Control in the ER

Characterization of Early EDEM1 Protein Maturation Events and Their Functional Implications

The role of autophagy in endoplasmic reticulum stress-induced pancreatic β cell death

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