Targeted deubiquitination rescues distinct trafficking-deficient ion channelopathies

Kanner, Scott A.; Shuja, Zunaira; Choudhury, Papiya; Jain, Ananya; Colecraft, Henry M.

doi:10.1038/s41592-020-00992-6

Cited by 44 publications

(43 citation statements)

References 62 publications

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“…Neither aided G2029R trafficking; but for Kv11.1 channels only a subset of mutants could be rescued 22 by the respective treatments. Nevertheless, it is plausible that other Piezo1 mutants may be rescuable using alternative approaches 54 or pharmacological chaperones. N-glycosylation status can also be used in co-expression studies to interrogate the impact of disease-linked variants on the WT protein, thus mimicking heterozygosity.…”

Section: Discussionmentioning

confidence: 99%

Modified N-linked glycosylation status predicts trafficking defective human Piezo1 channel mutations

Cheng

et al. 2020

Preprint

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Mechanosensitive channels are integral membrane proteins that sense mechanical stimuli. Like all membrane proteins, they pass through biosynthetic quality control in the endoplasmic reticulum and Golgi that results in them reaching their destination at the plasma membrane. Here we show that N-linked glycosylation of two highly conserved asparagine residues in the cap region of mechanosensitive Piezo1 channels are necessary for the mature protein to reach the plasma membrane. Both mutation of these asparagines (N2294Q/N2331Q) and treatment with an enzyme that hydrolyses N-linked oligosaccharides (PNGaseF) eliminates the fully glycosylated mature Piezo1 protein. The N-glycans in the cap are a pre-requisite for higher-order glycosylation in the propeller regions, which are present in loops that are essential for mechanotransduction. Importantly, trafficking-defective Piezo1 variants linked to generalized lymphatic dysplasia and bicuspid aortic valve display reduced fully N-glycosylated protein. The higher order glycosylation status in vitro correlates with efficient membrane trafficking and will aid in determining the functional impact of Piezo1 variants of unknown significance.

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Section: Discussionmentioning

confidence: 99%

Modified N-linked glycosylation status predicts trafficking defective human Piezo1 channel mutations

Cheng

et al. 2020

Preprint

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“…This was tested with an engineered deubiquitinase that enables selective ubiquitin chain removal from target proteins to rescue the functional expression of trafficking defective ion channels that underlie either LQT1 or CF. 234 The authors of the study showed that targeted deubiquitination via engineered deubiquitinases provides a powerful protein stabilization method that not only corrects diverse disease caused by impaired ion channel trafficking (LQT1 and CF), but also introduces a new tool for deconstructing the ubiquitin code in situ. 234 …”

Section: Novel Strategies To Study Ion Channel Dysfunction and Drug-specific Therapies In Lqt1 Lqt2 And Lqt3 Syndromesmentioning

confidence: 99%

“… 234 The authors of the study showed that targeted deubiquitination via engineered deubiquitinases provides a powerful protein stabilization method that not only corrects diverse disease caused by impaired ion channel trafficking (LQT1 and CF), but also introduces a new tool for deconstructing the ubiquitin code in situ. 234 …”

Section: Novel Strategies To Study Ion Channel Dysfunction and Drug-specific Therapies In Lqt1 Lqt2 And Lqt3 Syndromesmentioning

confidence: 99%

Long QT syndrome – Bench to bedside

Ponce-Balbuena

Deschênes

2021

Heart Rhythm O2

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Long QT syndrome (LQTS) is a cardiovascular disorder characterized by an abnormality in cardiac repolarization leading to a prolonged QT interval and T-wave irregularities on the surface electrocardiogram. It is commonly associated with syncope, seizures, susceptibility to torsades de pointes, and risk for sudden death. LQTS is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. The availability of therapy for this lethal disease emphasizes the importance of early and accurate diagnosis. Additionally, understanding of the molecular mechanisms underlying LQTS could help to optimize genotype-specific treatments to prevent deaths in LQTS patients. In this review, we briefly summarize current knowledge regarding molecular underpinning of LQTS, in particular focusing on LQT1, LQT2, and LQT3, and discuss novel strategies to study ion channel dysfunction and drug-specific therapies in LQT1, LQT2, and LQT3 syndromes.

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“…It has also encouraged others to “think outside of the box” on innovative ways that macromolecule function can be modulated. Within the past few years, strategies have been developed to induce the deubiquitination of POIs ( 175 ). Beyond this, scientists have used chimeric molecules to induce phosphorylation (Phosphorylation-Inducing Chimeras, PHIC) ( 176 ).…”

Section: Summary and Perspectivementioning

confidence: 99%

Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs

Alabi

Crews

2021

Journal of Biological Chemistry

133

122

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Of late, targeted protein degradation (TPD) has surfaced as a novel and innovative chemical tool and therapeutic modality. By co-opting protein degradation pathways, TPD facilitates complete removal of the protein molecules from within or outside the cell. While the pioneering Proteolysis-Targeting Chimera (PROTAC) technology and molecular glues hijack the ubiquitin-proteasome system, newer modalities co-opt autophagy or the endo-lysosomal pathway. Using this mechanism, TPD is posited to largely expand the druggable space far beyond small-molecule inhibitors. In this review, we discuss the major advances in TPD, highlight our current understanding, and explore outstanding questions in the field.

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Targeted deubiquitination rescues distinct trafficking-deficient ion channelopathies

Cited by 44 publications

References 62 publications

Modified N-linked glycosylation status predicts trafficking defective human Piezo1 channel mutations

Modified N-linked glycosylation status predicts trafficking defective human Piezo1 channel mutations

Long QT syndrome – Bench to bedside

Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs

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