Endoplasmic Reticulum-Targeted Subunit Toxins Provide a New Approach to Rescue Misfolded Mutant Proteins and Revert Cell Models of Genetic Diseases

Adnan, Humaira; Zhang, Zhenbo; Park, Hyun-Joo; Tailor, Chetankumar S.; Che, Clare; Kamani, Mustafa; Spitalny, George L.; Binnington, Beth; Lingwood, Clifford A.

doi:10.1371/journal.pone.0166948

Cited by 11 publications

(16 citation statements)

References 105 publications

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“…Therefore, ERAD-derived toxins could be used directly in therapy of certain genetic protein misfolding diseases. In ERAD-dependent genetic diseases mutant proteins are targeted to the ER translocons, retrotranslocated to the cytosol and prematurely degraded by the proteasome [269,270]. It was assumed that inhibition of ERAD could partially improve impaired intracellular transport and positively affect subcellular localization and enzymatic activities of mutated enzymes.…”

Section: Discussionmentioning

confidence: 99%

Toxins Utilize the Endoplasmic Reticulum-Associated Protein Degradation Pathway in Their Intoxication Process

Nowakowska-Gołacka

Sominka

Sowa-Rogozińska

et al. 2019

IJMS

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Several bacterial and plant AB-toxins are delivered by retrograde vesicular transport to the endoplasmic reticulum (ER), where the enzymatically active A subunit is disassembled from the holotoxin and transported to the cytosol. In this process, toxins subvert the ER-associated degradation (ERAD) pathway. ERAD is an important part of cellular regulatory mechanism that targets misfolded proteins to the ER channels, prior to their retrotranslocation to the cytosol, ubiquitination and subsequent degradation by a protein-degrading complex, the proteasome. In this article, we present an overview of current understanding of the ERAD-dependent transport of AB-toxins to the cytosol. We describe important components of ERAD and discuss their significance for toxin transport. Toxin recognition and disassembly in the ER, transport through ER translocons and finally cytosolic events that instead of overall proteasomal degradation provide proper folding and cytotoxic activity of AB-toxins are discussed as well. We also comment on recent reports presenting medical applications for toxin transport through the ER channels.

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Section: Discussionmentioning

confidence: 99%

Toxins Utilize the Endoplasmic Reticulum-Associated Protein Degradation Pathway in Their Intoxication Process

Nowakowska-Gołacka

Sominka

Sowa-Rogozińska

et al. 2019

IJMS

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“…Another very interesting therapeutic approach provided by CT consists of targeting and temporarily occupying the ERAD pathway, thus rescuing deleterious phenotypes in genetic diseases with mutations that lead to the premature degradation of a misfolded protein. Adnan et al illustrated this strategy using inactivated Shiga toxin and CT in cells derived from patients with an F508 deletion in cystic fibrosis transmembrane conductance regulator (CFTR) bronchiolar epithelia, a mutation in a plasma membrane chloride channel that leads to cystic fibrosis [ 36 ]. The inactivated toxins were able to induce 5–10-fold increases in protein levels, 20-fold increases in cell surface expression, and 2-fold chloride transport through the membrane with no apparent cytotoxicity.…”

Section: Cholera Toxinmentioning

confidence: 99%

“…Use of an inactive CT to temporarily occupy the ERAD-associated translocation machinery in the treatments of genetic protein misfolding diseases [ 36 ]…”

Section: Figurementioning

confidence: 99%

Harnessing the Membrane Translocation Properties of AB Toxins for Therapeutic Applications

Piot

Goot

Sergeeva

2021

Toxins

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Over the last few decades, proteins and peptides have become increasingly more common as FDA-approved drugs, despite their inefficient delivery due to their inability to cross the plasma membrane. In this context, bacterial two-component systems, termed AB toxins, use various protein-based membrane translocation mechanisms to deliver toxins into cells, and these mechanisms could provide new insights into the development of bio-based drug delivery systems. These toxins have great potential as therapies both because of their intrinsic properties as well as the modular characteristics of both subunits, which make them highly amenable to conjugation with various drug classes. This review focuses on the therapeutical approaches involving the internalization mechanisms of three representative AB toxins: botulinum toxin type A, anthrax toxin, and cholera toxin. We showcase several specific examples of the use of these toxins to develop new therapeutic strategies for numerous diseases and explain what makes these toxins promising tools in the development of drugs and drug delivery systems.

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“…Targeting the affected enzyme: TPP1 enhancer, chaperone, enzyme/ chaperone co-administration [37][38][39][40][41][42] Gemfibrozil…”

Section: Mps I Cystinosismentioning

confidence: 99%

FDA orphan drug designations for lysosomal storage disorders – a cross-sectional analysis

et al. 2020

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To provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat lysosomal storage disorders (LSDs). Methods Assessment of the drug pipeline through analysis of the FDA database for orphan drug designations with descriptive and comparative statistics. Results Between 1983 and 2019, 124 orphan drug designations were granted by the FDA for compounds intended to treat 28 lysosomal storage diseases. Orphan drug designations focused on Gaucher disease (N = 16), Pompe disease (N = 16), Fabry disease (N = 10), MPS II (N = 10), MPS I (N = 9), and MPS IIIA (N = 9), and included enzyme replacement therapies, gene therapies, and small molecules, and others. Twenty-three orphan drugs were approved for the treatment of 11 LSDs. Gaucher disease (N = 6), cystinosis (N = 5), Pompe disease (N = 3), and Fabry disease (N = 2) had multiple approvals, CLN2, LAL-D, MPS I, II, IVA, VI, and VII one approval each. This is an increase of nine more approved drugs and four more treatable LSDs (CLN2, MPS VII, LAL-D, and MPS IVA) since 2013. Mean time between orphan drug designation and FDA approval was 89.7 SD 55.00 (range 8-203, N = 23) months. Conclusions The drug development pipeline for LSDs is growing and evolving, with increased focus on diverse small-molecule targets and gene therapy. CLN2 was the first and only LSD with an approved therapy directly targeted to the brain. Newly approved products included "metoo"-enzymes and innovative compounds such as the first pharmacological chaperone for the treatment of Fabry disease.

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Endoplasmic Reticulum-Targeted Subunit Toxins Provide a New Approach to Rescue Misfolded Mutant Proteins and Revert Cell Models of Genetic Diseases

Cited by 11 publications

References 105 publications

Toxins Utilize the Endoplasmic Reticulum-Associated Protein Degradation Pathway in Their Intoxication Process

Toxins Utilize the Endoplasmic Reticulum-Associated Protein Degradation Pathway in Their Intoxication Process

Harnessing the Membrane Translocation Properties of AB Toxins for Therapeutic Applications

FDA orphan drug designations for lysosomal storage disorders – a cross-sectional analysis

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