Protein quality control—linking the unfolded protein response to disease

Cyr, Douglas M.; Hebert, Daniel N.

doi:10.1038/embor.2009.224

Cited by 7 publications

(3 citation statements)

References 18 publications

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“…1 ) may be because of (i) differential protein vs. RNA turnover, (ii) no rate-limitation of mRNA levels with regard to protein synthesis, (iii) these proteins are part of multigene family, while antibody recognizes shared epitopes, or (iv) species differences as antibodies were raised against and validated for human, not Chinese hamster antigens. Interestingly, we found substantial upregulation of BiP, the ER UPR stress sensor, 34 which showed nuclear and cytoplasmic localization in A23 CBS I278T or R125Q cells compared to weak nuclear localization in A23 CBS WT cells ( Fig. 2 ).…”

Section: Discussionmentioning

confidence: 84%

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Genetic and Pharmacological Modulation of Cellular Proteostasis Leads to Partial Functional Rescue of Homocystinuria-Causing Cystathionine-Beta Synthase Variants

Collard,

Majtan

2023

Molecular and Cellular Biology

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Homocystinuria (HCU), an inherited metabolic disorder caused by lack of cystathionine beta-synthase (CBS) activity, is chiefly caused by misfolding of single amino acid residue missense pathogenic variants. Previous studies showed that chemical, pharmacological chaperones or proteasome inhibitors could rescue function of multiple pathogenic CBS variants; however, the underlying mechanisms remain poorly understood. Using Chinese hamster DON fibroblasts devoid of CBS and stably overexpressing human WT or mutant CBS, we showed that expression of pathogenic CBS variant mostly dysregulates gene expression of small heat shock proteins HSPB3 and HSPB8 and members of HSP40 family. Endoplasmic reticulum stress sensor BiP was found upregulated with CBS I278T variant associated with proteasomes suggesting proteotoxic stress and degradation of misfolded CBS. Co-expression of the main effector HSP70 or master regulator HSF1 rescued steady-state levels of CBS I278T and R125Q variants with partial functional rescue of the latter. Pharmacological proteostasis modulators partially rescued expression and activity of CBS R125Q likely due to reduced proteotoxic stress as indicated by decreased BiP levels and promotion of refolding as indicated by induction of HSP70. In conclusion, targeted manipulation of cellular proteostasis may represent a viable therapeutic approach for the permissive pathogenic CBS variants causing HCU.

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Section: Discussionmentioning

confidence: 84%

“…BiP upregulation may actually represent cellular compensatory action to prevent UPR, because BiP acts as a suppressor of double‑stranded RNA‑dependent protein kinase‑like ER (PERK), activating transcription factor 6 (ATF6) and inositol‑requiring enzyme 1 (IRE1) signaling pathways. 34 …”

Section: Discussionmentioning

confidence: 99%

Genetic and Pharmacological Modulation of Cellular Proteostasis Leads to Partial Functional Rescue of Homocystinuria-Causing Cystathionine-Beta Synthase Variants

Collard,

Majtan

2023

Molecular and Cellular Biology

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“…Utilization of these two alternative pathways to dispose of pathogenic CBS variants may potentially be related to the induction of ER stress due to CBS misfolding and aggregation (or formation of higher‐molecular weight complexes). Previously we showed that the expression of CBS I278T variant significantly upregulates expression of several cytoplasmic molecular chaperones and substantially increases the expression of BiP, an ER sensor of unfolded protein response (Collard & Majtan, 2023 ; Cyr & Hebert, 2009 ) indicating involvement of ER in proteostasis of HCU CBS variants. ALP is the second main pathway for protein degradation after UPS, typically used for protein aggregates and organelles (Siva Sankar & Dengjel, 2020 ).…”

Section: Discussionmentioning

confidence: 96%

Cellular turnover and degradation of the most common missense cystathionine beta‐synthase variants causing homocystinuria

Mijatovic,

Ascenção,

Szabo

et al. 2024

Protein Science

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Homocystinuria (HCU) due to cystathionine beta‐synthase (CBS) deficiency is the most common inborn error of sulfur amino acid metabolism. Recent work suggests that missense pathogenic mutations—regardless of their topology—cause instability of the C‐terminal regulatory domain, which likely translates into CBS misfolding, impaired assembly, and loss of function. However, it is unknown how instability of the regulatory domain translates into cellular CBS turnover and which degradation pathways are involved in CBS proteostasis. Here, we developed a human HEK293‐based cellular model lacking intrinsic CBS and stably overexpressing wild‐type (WT) CBS or its 10 most common missense HCU mutants. We found that HCU mutants, except the I278T variant, expressed similarly or better than CBS WT, with some of them showing impaired oligomerization, activity and response to allosteric activator S‐adenosylmethionine. Cellular stability of all HCU mutants, except P49L and A114V, was significantly lower than the stability of CBS WT, suggesting their increased degradation. Ubiquitination analysis of CBS WT and two representative CBS mutants (T191M and I278T) showed that proteasomal degradation is the major pathway for CBS disposal, with a minor involvement of lysosomal‐autophagic and endoplasmic reticulum‐associated degradation (ERAD) pathways for HCU mutants. Proteasomal inhibition significantly increased the half‐life and activity of T191M and I278T CBS mutants. Lysosomal and ERAD inhibition had only a minor impact on CBS turnover, but ERAD inhibition rescued the activity of T191M and I278T CBS mutants similarly as proteasomal inhibition. In conclusion, the present study provides new insights into proteostasis of CBS in HCU.

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Fight Back: Adaptive Responses to Toxicant Exposure

Burcham

2013

An Introduction to Toxicology

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Protein quality control—linking the unfolded protein response to disease

Abstract: The proper folding of proteins is essential for cellular homeostasis and prevention of an ever‐growing number of diseases. Here, the authors highlight recent breakthroughs in the study of the unfolded protein response and new strategies to combat the diseases caused by its malfunction.

Cited by 7 publications

References 18 publications

Genetic and Pharmacological Modulation of Cellular Proteostasis Leads to Partial Functional Rescue of Homocystinuria-Causing Cystathionine-Beta Synthase Variants

Genetic and Pharmacological Modulation of Cellular Proteostasis Leads to Partial Functional Rescue of Homocystinuria-Causing Cystathionine-Beta Synthase Variants

Cellular turnover and degradation of the most common missense cystathionine beta‐synthase variants causing homocystinuria

Fight Back: Adaptive Responses to Toxicant Exposure

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