Coping with Protein Quality Control Failure

Pilla, Esther; Schneider, Kim; Bertolotti, Anne

doi:10.1146/annurev-cellbio-111315-125334

Cited by 71 publications

(61 citation statements)

References 168 publications

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“…It is considered the site where the gene products are subjected to a stringent quality control that selects structurally imperfect gene products for degradation, thus resulting in loss-of-function diseases. As such, modulation of processes occurring within the ER such as posttranslational modifications, chaperone-assisted protein folding, selection for secretion, or for degradation are strong candidates for therapeutic intervention, and chemical and pharmacologic chaperones that enhance folding of mutant gene products are entering the clinics (Noack et al, 2014;Pilla et al, 2017). Our data reveal that passing ER quality control and arrival at the intracellular site of destination might not be sufficient to warrant healthy status.…”

Section: Discussionmentioning

confidence: 92%

Endoplasmic Reticulum and Lysosomal Quality Control of Four Nonsense Mutants of Iduronate 2-Sulfatase Linked to Hunter's Syndrome

Marazza

Galli²,

Fasana³

et al. 2020

DNA and Cell Biology

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Hunter's syndrome (mucopolysaccharidosis type II) is a rare X-linked lysosomal storage disorder caused by mutations in the iduronate-2-sulfatase (IDS) gene. Motivated by the case of a child affected by this syndrome, we compared the intracellular fate of wild-type IDS (IDS WT ) and four nonsense mutations of IDS (IDS L482X , IDS Y452X , IDS R443X , and IDS W337X ) generating progressively shorter forms of IDS associated with mild to severe forms of the disease. Our analyses revealed formylation of all forms of IDS at cysteine 84, which is a prerequisite for enzymatic activity. After formylation, IDS WT was transported within lysosomes, where it was processed in the mature form of the enzyme. The length of disease-causing deletions correlated with gravity of the folding and transport phenotype, which was anticipated by molecular dynamics analyses. The shortest form of IDS, IDS W337X , was retained in the endoplasmic reticulum (ER) and degraded by the ubiquitin-proteasome system. IDS R443X , IDS Y452X , and IDS L482X passed ER quality control and were transported to the lysosomes, but failed lysosomal quality control, resulting in their rapid clearance and in loss-of-function phenotype. Failure of ER quality control inspection is an established cause of loss of function observed in protein misfolding diseases. Our data reveal that fulfillment of ER requirements might not be sufficient, highlight lysosomal quality control as the distal station to control lysosomal enzymes fitness and pave the way for alternative therapeutic interventions.

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Section: Discussionmentioning

confidence: 92%

Endoplasmic Reticulum and Lysosomal Quality Control of Four Nonsense Mutants of Iduronate 2-Sulfatase Linked to Hunter's Syndrome

Marazza

Galli²,

Fasana³

et al. 2020

DNA and Cell Biology

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“…A key function of the proteasome is the destruction of damaged and misfolded proteins. Deficits in proteasome function cause adult-onset neurodegenerative diseases and may be a general feature of decline in cellular and organismal function during aging (Pilla et al, 2017;Saez and Vilchez, 2014). Dissecting how cells maintain homeostasis during challenges to the proteasome may provide insights into how the system fails during aging and disease.…”

Section: Introductionmentioning

confidence: 99%

Protein Sequence Editing of SKN-1A/Nrf1 by Peptide:N-Glycanase Controls Proteasome Gene Expression

Lehrbach

Breen

Ruvkun

2019

Cell

120

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Graphical Abstract Highlights d PNGase edits glycosylated Asn residues of the SKN-1A transcription factor to Asp d These edits are required for SKN-1A to regulate proteasome subunit genes d Sequence-edited SKN-1A enhances proteostasis d Edits cause ER-targeted and cytosolic SKN-1 isoforms to regulate distinct genes SUMMARYThe proteasome mediates selective protein degradation and is dynamically regulated in response to proteotoxic challenges. SKN-1A/Nrf1, an endoplasmic reticulum (ER)-associated transcription factor that undergoes N-linked glycosylation, serves as a sensor of proteasome dysfunction and triggers compensatory upregulation of proteasome subunit genes. Here, we show that the PNG-1/NGLY1 peptide:N-glycanase edits the sequence of SKN-1A protein by converting particular N-glycosylated asparagine residues to aspartic acid. Genetically introducing aspartates at these N-glycosylation sites bypasses the requirement for PNG-1/NGLY1, showing that protein sequence editing rather than deglycosylation is key to SKN-1A function. This pathway is required to maintain sufficient proteasome expression and activity, and SKN-1A hyperactivation confers resistance to the proteotoxicity of human amyloid beta peptide. Deglycosylationdependent protein sequence editing explains how ER-associated and cytosolic isoforms of SKN-1 perform distinct cytoprotective functions corresponding to those of mammalian Nrf1 and Nrf2. Thus, we uncover an unexpected mechanism by which N-linked glycosylation regulates protein function and proteostasis.

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“…Proteins must fold into their unique native structures to be functional, and the process of synthesis is tightly regulated to ensure efficient processing (for reviews, see Gloge et al, 2014;Pechmann et al, 2013). Once they are synthesized, the structure of native proteins is not rigid, and a network of chaperones and degradation machineries maintain the integrity of the proteome, constituting the protein quality-control (PQC) system meant to recognize, refold, and degrade aberrant proteins to maintain protein homeostasis, also known as proteostasis (for reviews, see Balchin et al, 2016;Kim et al, 2013;Pilla et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Chaperone-Facilitated Aggregation of Thermo-Sensitive Proteins Shields Them from Degradation during Heat Stress

et al. 2020

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Graphical Abstract Highlights d Misfolded proteins collapse into protein aggregate centers (PACs) upon heat shock d PAC formation requires the Hsp40 chaperone Mas5 d PACs serve as seed for the nucleation of stress granules at severe temperatures d The fate of PACs is refolding, as they protect misfolded proteins from degradation SUMMARY Cells have developed protein quality-control strategies to manage the accumulation of misfolded substrates during heat stress. Using a soluble reporter of misfolding in fission yeast, Rho1.C17R-GFP, we demonstrate that upon mild heat shock, the reporter collapses in protein aggregate centers (PACs). They contain and/or require several chaperones, such as Hsp104, Hsp16, and the Hsp40/70 couple Mas5/ Ssa2. Stress granules do not assemble at mild temperatures and, therefore, are not required for PAC formation; on the contrary, PACs may serve as nucleation centers for the assembly of stress granules. In contrast to the general belief, the dominant fate of these PACs is not degradation, and the aggregated reporter can be disassembled by chaperones and recovers native structure and activity. Using mass spectrometry, we show that thermo-unstable endogenous proteins form PACs as well. In conclusion, formation of PACs during heat shock is a chaperone-mediated adaptation strategy. Image Studio Lite Li-Cor Biosciences https://www.licor.com/bio/ image-studio-lite/ e1

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Coping with Protein Quality Control Failure

Cited by 71 publications

References 168 publications

Endoplasmic Reticulum and Lysosomal Quality Control of Four Nonsense Mutants of Iduronate 2-Sulfatase Linked to Hunter's Syndrome

Endoplasmic Reticulum and Lysosomal Quality Control of Four Nonsense Mutants of Iduronate 2-Sulfatase Linked to Hunter's Syndrome

Protein Sequence Editing of SKN-1A/Nrf1 by Peptide:N-Glycanase Controls Proteasome Gene Expression

Chaperone-Facilitated Aggregation of Thermo-Sensitive Proteins Shields Them from Degradation during Heat Stress

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