The Dfm1 Derlin Is Required for ERAD Retrotranslocation of Integral Membrane Proteins

Neal, Sonya E.; Jaeger, Philipp A.; Duttke, Sascha H.; Benner, Christopher; Glass, Christopher K.; Ideker, Trey; Hampton, Randolph Y.

doi:10.1016/j.molcel.2018.02.014

Cited by 42 publications

(80 citation statements)

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“…In summary, here we uncover an ancestral membrane‐associated degradation mechanism including a substrate receptor/protease and processive degradative dislocase and protease. This is conceptually remarkably similar to the process of ERAD in which rhomboid pseudoproteases Derlins co‐operate with ubiquitin E3 ligases such as Hrd1, the AAA ATPase p97/VCP and the proteasome, in dislocating transmembrane proteins from the membranes of endoplasmic reticulum and degrading them (Neal et al , ; Ticha et al , ). Our work emphasises that even the active rhomboid proteases can have pseudoprotease functions, and suggests that the balance between their protease and pseudoprotease roles may vary.…”

Section: Discussionmentioning

confidence: 89%

“…It is conceivable that with a more efficient and specialised dislocation machinery in higher organisms, the requirement for protease activity of the rhomboid‐like protein (Derlin) could become less important, while the adaptor function becoming key. This logic would explain the particularly high occurrence of pseudoproteases in the rhomboid superfamily, which includes Derlins that are well‐known essential components of the eukaryotic substrate recognition and dislocation machinery in ERAD (Neal et al , ).…”

Section: Discussionmentioning

confidence: 99%

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Rhomboid intramembrane protease YqgP licenses bacterial membrane protein quality control as adaptor of FtsH AAA protease

et al. 2020

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Magnesium homeostasis is essential for life and depends on magnesium transporters, whose activity and ion selectivity need to be tightly controlled. Rhomboid intramembrane proteases pervade the prokaryotic kingdom, but their functions are largely elusive. Using proteomics, we find that Bacillus subtilis rhomboid protease YqgP interacts with the membrane-bound ATP-dependent processive metalloprotease FtsH and cleaves MgtE, the major highaffinity magnesium transporter in B. subtilis. MgtE cleavage by YqgP is potentiated in conditions of low magnesium and high manganese or zinc, thereby protecting B. subtilis from Mn 2+ /Zn 2+ toxicity. The N-terminal cytosolic domain of YqgP binds Mn 2+ and Zn 2+ ions and facilitates MgtE cleavage. Independently of its intrinsic protease activity, YqgP acts as a substrate adaptor for FtsH, a function that is necessary for degradation of MgtE. YqgP thus unites protease and pseudoprotease function, hinting at the evolutionary origin of rhomboid pseudoproteases such as Derlins that are intimately involved in eukaryotic ER-associated degradation (ERAD). Conceptually, the YqgP-FtsH system we describe here is analogous to a primordial form of "ERAD" in bacteria and exemplifies an ancestral function of rhomboid-superfamily proteins.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Rhomboid intramembrane protease YqgP licenses bacterial membrane protein quality control as adaptor of FtsH AAA protease

et al. 2020

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“…The reporters were expressed under tetracycline-regulated control ( Figure 1B) to permit reporter silencing during cell line selection and propagation, thereby minimizing the potential for adaptive changes (Neal et al, 2018). Basal fluorescence in clonal reporter K562 cell lines was indistinguishable from untransfected cells but increased substantially and in proportion to protein halflife following induction with doxycycline (dox) (Figures 1B and S1B).…”

Section: Resultsmentioning

confidence: 99%

Genome-wide CRISPR Analysis Identifies Substrate-Specific Conjugation Modules in ER-Associated Degradation

et al. 2019

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Graphical Abstract Highlights d A novel genetic screening method reports quantitative protein degradation rates d Systems-level analysis deconvolves substrate specificity in mammalian ERAD d Ricin A chain exploits a ''fast track'' route through the Hrd1 dislocon d Cytosolic ubiquitin ligases conjugate branched or mixed chains to promote ERAD SUMMARYThe ubiquitin proteasome system (UPS) maintains the integrity of the proteome by selectively degrading misfolded or mis-assembled proteins, but the rules that govern how conformationally defective proteins in the secretory pathway are selected from the structurally and topologically diverse constellation of correctly folded membrane and secretory proteins for efficient degradation by cytosolic proteasomes is not well understood. Here, we combine parallel pooled genome-wide CRISPR-Cas9 forward genetic screening with a highly quantitative and sensitive protein turnover assay to discover a previously undescribed collaboration between membraneembedded cytoplasmic ubiquitin E3 ligases to conjugate heterotypic branched or mixed ubiquitin (Ub) chains on substrates of endoplasmic-reticulumassociated degradation (ERAD). These findings demonstrate that parallel CRISPR analysis can be used to deconvolve highly complex cell biological processes and identify new biochemical pathways in protein quality control.

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“…The latter are membrane proteins that exhibit the rhomboid fold, but have lost their catalytic activity during evolution, while retaining or developing new functions such as the specific recognition or dislocation of proteins from the membrane (Lemberg & Adrain, ). Likewise, derlins act as rhomboid pseudoproteases in eukaryotic ERAD of both soluble and integral membrane proteins (Greenblatt et al , ; Neal et al , ). The observation that the B. subtilis YqgP.S288A active site mutant mimics a pseudoprotease function implies that the protease mechanism and rhomboid‐assisted recognition of a membrane protein for processing by the AAA protease FtsH follow shared principles (Began et al , ).…”

Section: Rhomboid Proteases and Pseudoproteases Target Proteins For Dmentioning

confidence: 99%

Derlins with scissors: primordial ERAD in bacteria

Knopf

Lemberg

2020

The EMBO Journal

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Rhomboid intramembrane serine proteases are present in all kingdoms of life, but as we do not know their substrates in many species, it remains puzzling why rhomboids are among the most‐conserved integral membrane proteins. Two new studies in The EMBO Journal by Began et al and Liu et al now link bacterial rhomboid proteases to membrane protein degradation, showing striking similarities to what is known about eukaryotic rhomboid family proteins, thus pointing toward a conserved membrane surveillance mechanism.

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The Dfm1 Derlin Is Required for ERAD Retrotranslocation of Integral Membrane Proteins

Cited by 42 publications

References 0 publications

Rhomboid intramembrane protease YqgP licenses bacterial membrane protein quality control as adaptor of FtsH AAA protease

Rhomboid intramembrane protease YqgP licenses bacterial membrane protein quality control as adaptor of FtsH AAA protease

Genome-wide CRISPR Analysis Identifies Substrate-Specific Conjugation Modules in ER-Associated Degradation

Derlins with scissors: primordial ERAD in bacteria

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