New drugs in cystic fibrosis: what has changed in the last decade?

Roda, Juliana; Pinto-Silva, Catarina; Silva, Iris A I; Maia, Carla; Almeida, Susana Marta; Ferreira, Ricardo; Oliveira, Guiomar

doi:10.1177/20406223221098136

Cited by 6 publications

(2 citation statements)

References 56 publications

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“…An alternative approach would be to develop small molecule stabilizers/correctors that through binding to the native conformation could block PQC-linked degradation and reactivate certain pathogenic variants. Indeed such drugs have been successfully developed and implemented for cystic fibrosis 88 .…”

Section: Discussionmentioning

confidence: 99%

Deep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants

Grønbæk-Thygesen,

Voutsinos,

Johansson

et al. 2024

Nat Commun

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Unstable proteins are prone to form non-native interactions with other proteins and thereby may become toxic. To mitigate this, destabilized proteins are targeted by the protein quality control network. Here we present systematic studies of the cytosolic aspartoacylase, ASPA, where variants are linked to Canavan disease, a lethal neurological disorder. We determine the abundance of 6152 of the 6260 ( ~ 98%) possible single amino acid substitutions and nonsense ASPA variants in human cells. Most low abundance variants are degraded through the ubiquitin-proteasome pathway and become toxic upon prolonged expression. The data correlates with predicted changes in thermodynamic stability, evolutionary conservation, and separate disease-linked variants from benign variants. Mapping of degradation signals (degrons) shows that these are often buried and the C-terminal region functions as a degron. The data can be used to interpret Canavan disease variants and provide insight into the relationship between protein stability, degradation and cell fitness.

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Section: Discussionmentioning

confidence: 99%

Deep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants

Grønbæk-Thygesen,

Voutsinos,

Johansson

et al. 2024

Nat Commun

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show abstract

Section: Discussionmentioning

confidence: 99%

Deep mutational scanning reveals a tight correlation between protein degradation and toxicity of thousands of non-native aspartoacylase protein variants

Grønbæk-Thygesen,

Voutsinos,

Johansson

et al. 2023

Preprint

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When the structural stability of a protein is compromised, the protein may form non-native interactions with other cell proteins and thus becomes a hazard to the cell. To mitigate this danger, destabilized proteins are targeted by the cellular protein quality control (PQC) network, which either corrects the folding defect or targets the protein for degradation. However, the details of how the protein folding and degradation systems collaborate to combat potentially toxic non-native proteins are unknown. To address this issue, we performed systematic studies on destabilized variants of the cytosolic aspartoacylase, ASPA, where loss-of-function variants are linked to Canavan’s disease, an autosomal recessive and lethal neurological disorder, characterized by the spongy degeneration of the white matter in the brain. Using Variant Abundance by Massively Parallel sequencing (VAMP-seq), we determined the abundance of 6152 out of the 6260 (∼98%) possible single-site missense and nonsense ASPA variants in cultured human cells. The majority of the low abundance ASPA variants are degraded through the ubiquitin-proteasome system (UPS) and become toxic upon prolonged expression. Variant cellular abundance data correlates with predicted thermodynamic stability, evolutionary conservation, and separates most known disease-linked variants from benign variants. Systematic mapping of degradation signals (degrons) shows that inherent primary degrons in ASPA are located in buried regions, and reveals that the wild-type ASPA C-terminal region functions as a degron. Collectively, our data can be used to interpret Canavan’s disease variants and also offer mechanistic insight into how ASPA missense variants are targeted by the PQC system. These are essential steps towards future implementation of precision medicine for Canavan’s disease.

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Targeting ubiquitination machinery in cystic fibrosis: Where do we stand?

Okiyoneda,

Borgo,

Bosello Travain

et al. 2024

Cell. Mol. Life Sci.

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Cystic Fibrosis (CF) is a genetic disease caused by mutations in CFTR gene expressing the anion selective channel CFTR located at the plasma membrane of different epithelial cells. The most commonly investigated variant causing CF is F508del. This mutation leads to structural defects in the CFTR protein, which are recognized by the endoplasmic reticulum (ER) quality control system. As a result, the protein is retained in the ER and degraded via the ubiquitin–proteasome pathway. Although blocking ubiquitination to stabilize the CFTR protein has long been considered a potential pharmacological approach in CF, progress in this area has been relatively slow. Currently, no compounds targeting this pathway have entered clinical trials for CF. On the other hand, the emergence of Orkambi initially, and notably the subsequent introduction of Trikafta/Kaftrio, have demonstrated the effectiveness of molecular chaperone-based therapies for patients carrying the F508del variant and even showed efficacy against other variants. These treatments directly target the CFTR variant protein without interfering with cell signaling pathways. This review discusses the limits and potential future of targeting protein ubiquitination in CF.

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New drugs in cystic fibrosis: what has changed in the last decade?

Cited by 6 publications

References 56 publications

Deep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants

Deep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants

Deep mutational scanning reveals a tight correlation between protein degradation and toxicity of thousands of non-native aspartoacylase protein variants

Targeting ubiquitination machinery in cystic fibrosis: Where do we stand?

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