Degradation of Trafficking-defective Long QT Syndrome Type II Mutant Channels by the Ubiquitin-Proteasome Pathway

Gong, Qiuming; Keeney, David; Molinari, Maurizio; Zhou, Zhengfeng

doi:10.1074/jbc.m502327200

Cited by 100 publications

(87 citation statements)

References 51 publications

(38 reference statements)

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“…Again, this is in agreement with the safe-by-design approach to nanomedicine development. 18 Since mature hERG1 K + channels remain at the plasma membrane with a half-life of ~10 hours, 99,100 we hypothesize that in our 24-hour experiments AuPEG_4 immobilized onto the cell membrane by active targeting of the Kv11.1 subunit were internalized into the cells during hERG1 channels degradation. In this phase, hERG1 channels are internalized in endocytic vesicles, tagged with ubiquitin, and then degraded in lysosomes, 89,101 thus making possible DOX to be released enzymatically from its nanocarrier.…”

mentioning

confidence: 99%

Targeted polyethylene glycol gold nanoparticles for the treatment of pancreatic cancer: from synthesis to proof-of-concept in vitro studies

Spadavecchia¹,

Movia²,

Moore³

et al. 2016

IJN

167

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International audienceThe main objective of this study was to optimize and characterize a drug delivery carrier for doxorubicin, intended to be intravenously administered, capable of improving the therapeutic index of the chemotherapeutic agent itself, and aimed at the treatment of pancreatic cancer. In light of this goal, we report a robust one-step method for the synthesis of dicarboxylic acid-terminated polyethylene glycol (PEG)-gold nanoparticles (AuNPs) and doxorubicin-loaded PEG-AuNPs, and their further antibody targeting (anti-Kv11.1 polyclonal antibody [pAb]). In in vitro proof-of-concept studies, we evaluated the influence of the nanocarrier and of the active targeting functionality on the anti-tumor efficacy of doxorubicin, with respect to its half-maximal effective concentration (EC50) and drug-triggered changes in the cell cycle. Our results demonstrated that the therapeutic efficacy of doxorubicin was positively influenced not only by the active targeting exploited through anti-Kv11.1-pAb but also by the drug coupling with a nanometer-sized delivery system, which indeed resulted in a 30-fold decrease of doxorubicin EC50, cell cycle blockage, and drug localization in the cell nuclei. The cell internalization pathway was strongly influenced by the active targeting of the Kv11.1 subunit of the human Ether-à-go-go related gene 1 (hERG1) channel aberrantly expressed on the membrane of pancreatic cancer cells. Targeted PEG-AuNPs were translocated into the lysosomes and were associated to an increased lysosomal function in PANC-1 cells. Additionally, doxorubicin release into an aqueous environment was almost negligible after 7 days, suggesting that drug release from PEG-AuNPs was triggered by enzymatic activity. Although preliminary, data gathered from this study have considerable potential in the application of safe-by-design nano-enabled drug-delivery systems (ie, nanomedicines) for the treatment of pancreatic cancer, a disease with a poor prognosis and one of the main current burdens of today’s health care bill of industrialized countries

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mentioning

confidence: 99%

Targeted polyethylene glycol gold nanoparticles for the treatment of pancreatic cancer: from synthesis to proof-of-concept in vitro studies

Spadavecchia¹,

Movia²,

Moore³

et al. 2016

IJN

167

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“…These mutations have been postulated to reduce functional rapidly activating delayed rectifier K + current through biophysical and/or biogenic mechanisms (16,(22)(23)(24)(25)(26)(27). In the former case, protein processing is normal and the protein is transported to the cell membrane, but its biophysical properties are altered.…”

Section: Discussionmentioning

confidence: 99%

Novel characteristics of a trafficking-defective G572R-hERG channel linked to hereditary long QT syndrome

Lian

Huang

Zhou

et al. 2010

Canadian Journal of Cardiology

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“…Overexpression of EDEM1 accelerates the extraction of proteins from the CNX binding cycle and their subsequent degradation by the proteasome (23,24). In contrast, knockdown of EDEM1 stabilizes glycosylated ERAD substrates (24,25). In addition to ERAD substrates, EDEM1 has been reported to associate with a number of quality control factors including CNX, SEL1L, ERdj5, ER mannosidase I, and Derlin-2/3 (23, 26 -29).…”

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confidence: 99%

Characterization of Early EDEM1 Protein Maturation Events and Their Functional Implications

Tamura

Cormier

Hebert

2011

Journal of Biological Chemistry

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The endoplasmic reticulum (ER) quality control factor EDEM1 associates with a number of ER proteins and ER-associated degradation (ERAD) substrates; however, an understanding of its role in ERAD is unclear. The early maturation events for EDEM1 including signal sequence cleavage and glycosylation were analyzed, and their relationship to the function of EDEM1 was determined. EDEM1 has five N-linked glycosylation sites with the most C-terminal site recognized poorly cotranslationally, resulting in the accumulation of EDEM1 containing four or five glycans. The fifth site was modified post-translationally when bypassed cotranslationally. Signal sequence cleavage of EDEM1 was found to be a slow and inefficient process. Signal sequence cleavage produced a soluble form of EDEM1 that efficiently associated with the oxidoreductase ERdj5 and most effectively accelerated the turnover of a soluble ERAD substrate. In contrast, a type-II membrane form of EDEM1 was generated when the signal sequence was uncleaved, creating an N-terminal transmembrane segment. The membrane form of EDEM1 efficiently associated with the ER membrane protein SEL1L and accelerated the turnover of a membrane-associated ERAD substrate. Together, these results demonstrated that signal sequence cleavage functionally regulated the association of EDEM1-soluble and membrane-integrated isoforms with distinct ERAD machinery and substrates.The signal hypothesis states that proteins are targeted to the eukaryotic secretory pathway by hydrophobic signal sequences that are frequently positioned at the N terminus of the protein (1). These proteins are cotranslationally targeted and translocated across the endoplasmic reticulum (ER) 2 membrane where the vast majority of the maturation process occurs. Maturation events include signal sequence cleavage, protein folding, covalent modification, and assembly (2). The ER contains a number of factors that aid in these steps for secretory and membrane proteins. As protein maturation is an error-prone process, the ER also possesses a quality control process that monitors the successfulness of these steps (3, 4). Quality control factors dedicated to the evaluation and sorting of maturing proteins target defective proteins for destruction by the cytoplasmic proteasome after their dislocation through the ER membrane by a process termed ER-associated degradation (ERAD). Although many of the players involved in ER quality control have been uncovered over the past decade, there is still much to be learned about the mechanism of the quality control process.Signal sequences that target proteins to the ER generally consist of the first 20 -30 amino acids of a protein organized into three domains (5). Signal sequences start with a basic N-terminal domain (N-domain) followed by an extended hydrophobic domain (H-domain; ϳ7-13 amino acids in length) and a polar domain (C-domain) that contains low molecular weight amino acids near the cleavage site. Recent evidence indicates that signal sequences do not solely provide transient targetin...

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Degradation of Trafficking-defective Long QT Syndrome Type II Mutant Channels by the Ubiquitin-Proteasome Pathway

Cited by 100 publications

References 51 publications

Targeted polyethylene glycol gold nanoparticles for the treatment of pancreatic cancer: from synthesis to proof-of-concept in vitro studies

Targeted polyethylene glycol gold nanoparticles for the treatment of pancreatic cancer: from synthesis to proof-of-concept in vitro studies

Novel characteristics of a trafficking-defective G572R-hERG channel linked to hereditary long QT syndrome

Characterization of Early EDEM1 Protein Maturation Events and Their Functional Implications

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