The mammalian UPR boosts glycoprotein ERAD by suppressing the proteolytic downregulation of ER mannosidase I

Termine, Daniel J.; Moremen, Kelley W.; Sifers, Richard N.

doi:10.1242/jcs.037291

Cited by 52 publications

(48 citation statements)

References 68 publications

(110 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Activation of the ATF6 pathway by preventing or delaying such an overload would reduce formation of the IBs. It has been reported recently that transcriptional elevation of an ERAD component, EDEM1, increases the efficiency of degradation of ATZ function, by maintaining ER mannosidase I function (29). Moreover, a mutation in the 3Ј-untranslated region of ER mannosidase I may accelerate the onset of the end stage liver disease (42).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Activating Transcription Factor 6 Limits Intracellular Accumulation of Mutant α1-Antitrypsin Z and Mitochondrial Damage in Hepatoma Cells

Smith

Granell

Salcedo-Sicilia

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

“…Active ATF6 Does Not Increase Autophagy-Degradation of ATZ has been proposed to occur by two pathways, ERAD and autophagy (17,22,24,25,28,29). In addition, ER stress can activate autophagy, which in turn may facilitate ATZ degradation (30).…”

Section: Hrd1-dependent Degradation Of Atz Occurs Within 30 Min Of Prmentioning

confidence: 99%

Activating Transcription Factor 6 Limits Intracellular Accumulation of Mutant α1-Antitrypsin Z and Mitochondrial Damage in Hepatoma Cells

Smith

Granell

Salcedo-Sicilia

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…6A, compare upper panel lanes 7 and 9 and lanes 10 and 12). The increase in mobility was likely caused by the mannosidase activity of EDEM1 or through its association with ER mannosidase I (29,40,41). The soluble form of EDEM1 was most effective at accelerating the turnover of the soluble ERAD substrate NHK.…”

Section: Post-translational N-linked Glycosylation Of the C-terminal mentioning

confidence: 99%

Characterization of Early EDEM1 Protein Maturation Events and Their Functional Implications

Tamura

Cormier

Hebert

2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

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...

show abstract

“…Accordingly, the degradation of yeast ERAD substrates is ER-MNSI dependent (Jakob et al, 1998;Clerc et al, 2009;Gauss et al, 2011). Moreover, in mammalian cells, ER-MNSI activity is tightly regulated, and changes in ER-MNSI levels affect ERAD of misfolded proteins Termine et al, 2009;Groisman et al, 2011). The situation in mammals appears even more complicated, as also trimming to Man 5 GlcNAc 2 -Man 6-GlcNAc 2 structures by Golgi-a-mannosidases has been described to occur during ERAD (Hosokawa et al, 2007;Avezov et al, 2008).…”

Section: Mns3 and Mns1/mns2 Are Not Involved In Erad Of Misfolded Brimentioning

confidence: 99%

Arabidopsis Class I α-Mannosidases MNS4 and MNS5 Are Involved in Endoplasmic Reticulum–Associated Degradation of Misfolded Glycoproteins

et al. 2014

View full text Add to dashboard Cite

To ensure that aberrantly folded proteins are cleared from the endoplasmic reticulum (ER), all eukaryotic cells possess a mechanism known as endoplasmic reticulum-associated degradation (ERAD). Many secretory proteins are N-glycosylated, and despite some recent progress, little is known about the mechanism that selects misfolded glycoproteins for degradation in plants. Here, we investigated the role of Arabidopsis thaliana class I a-mannosidases (MNS1 to MNS5) in glycan-dependent ERAD. Our genetic and biochemical data show that the two ER-resident proteins MNS4 and MNS5 are involved in the degradation of misfolded variants of the heavily glycosylated brassinosteroid receptor, BRASSINOSTEROID INSENSITIVE1, while MNS1 to MNS3 appear dispensable for this ERAD process. By contrast, N-glycan analysis of different mns mutant combinations revealed that MNS4 and MNS5 are not involved in regular N-glycan processing of properly folded secretory glycoproteins. Overexpression of MNS4 or MNS5 together with ER-retained glycoproteins indicates further that both enzymes can convert Glc 0-1 Man 8-9 GlcNAc 2 into N-glycans with a terminal a1,6-linked Man residue in the C-branch. Thus, MNS4 and MNS5 function in the formation of unique N-glycan structures that are specifically recognized by other components of the ERAD machinery, which ultimately results in the disposal of misfolded glycoproteins.

show abstract

The mammalian UPR boosts glycoprotein ERAD by suppressing the proteolytic downregulation of ER mannosidase I

Cited by 52 publications

References 68 publications

Activating Transcription Factor 6 Limits Intracellular Accumulation of Mutant α1-Antitrypsin Z and Mitochondrial Damage in Hepatoma Cells

Activating Transcription Factor 6 Limits Intracellular Accumulation of Mutant α1-Antitrypsin Z and Mitochondrial Damage in Hepatoma Cells

Characterization of Early EDEM1 Protein Maturation Events and Their Functional Implications

Arabidopsis Class I α-Mannosidases MNS4 and MNS5 Are Involved in Endoplasmic Reticulum–Associated Degradation of Misfolded Glycoproteins

Contact Info

Product

Resources

About