FKBP10 Depletion Enhances Glucocerebrosidase Proteostasis in Gaucher Disease Fibroblasts

Ong, Derrick Sek Tong; Wang, Ya Juan; Tan, Yun Lei; Mu, Ting

doi:10.1016/j.chembiol.2012.11.014

Cited by 16 publications

(11 citation statements)

References 57 publications

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“…Patient-derived GD fibroblasts were transfected with siRNA as previously described (Ong, et al, 2013). Briefly, fibroblasts were seeded in 6-well plates at approximately 2 × 10 5 cells per well and incubated at 37 °C overnight to reach 70–80% confluency before transient transfection using HiPerfect Transfection Reagent (Qiagen), according to the manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

ERdj3 Is an Endoplasmic Reticulum Degradation Factor for Mutant Glucocerebrosidase Variants Linked to Gaucher’s Disease

Tan

Genereux

Pankow

et al. 2014

Chemistry & Biology

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SUMMARY Gaucher’s disease (GD) is caused by mutations that compromise β-glucocerebrosidase (GCase) folding in the endoplasmic reticulum (ER), leading to excessive degradation instead of trafficking, which results in insufficient lysosomal function. We hypothesized that ER GCase interacting proteins play critical roles in making quality control decisions, i.e., facilitating ER-associated degradation (ERAD) instead of folding and trafficking. Utilizing GCase immunoprecipitation followed by mass spectrometry-based proteomics, we identified endogenous HeLa cell GCase protein interactors, including ERdj3, an ER resident Hsp40 not previously established to interact with GCase. Depleting ERdj3 reduced the rate of mutant GCase degradation in patient-derived fibroblasts, while increasing folding, trafficking and function by directing GCase to the pro-folding ER calnexin pathway. Inhibiting ERdj3-mediated mutant GCase degradation while simultaneously enhancing calnexin-associated folding, by way of a diltiazem-mediated increase in ER Ca2+ levels, yields a synergistic rescue of L444P GCase lysosomal function. Our findings suggest a combination therapeutic strategy for ameliorating GD.

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Section: Methodsmentioning

confidence: 99%

ERdj3 Is an Endoplasmic Reticulum Degradation Factor for Mutant Glucocerebrosidase Variants Linked to Gaucher’s Disease

Tan

Genereux

Pankow

et al. 2014

Chemistry & Biology

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“…Activation of the UPR using proteasome inhibitors such as MG-132 has been used to correct the trafficking of N-glycosylated mutant lysosomal enzymes associated with Gaucher and Tay-Sachs diseases 92 . Interestingly, enhanced glucocerebrosidase trafficking in MG-132–treated fibroblasts derived from patients with Gaucher disease was associated with down regulation of the expression level of the peptidyl proline isomerase FKBP10, suggesting that altering the finely choreographed interactions in the ER can be used to enhance mutant N-glycoprotein folding 95 . The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) has been used to correct the cellular trafficking of mutant alpha-1-antitrypsin and GABA A receptors associated with epilepsy 96, 97 .…”

Section: Defects In Glycoproteostasis Are Linked To Pathologymentioning

confidence: 99%

The intrinsic and extrinsic effects of N-linked glycans on glycoproteostasis

et al. 2014

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Proteins that traffic through the eukaryotic secretory pathway are commonly modified with N-linked carbohydrates. These bulky amphipathic modifications at asparagines intrinsically enhance solubility and folding energetics through carbohydrate-protein interactions. N-linked glycans can also extrinsically enhance glycoprotein folding by utilizing the glycoprotein homeostasis or “glycoproteostasis” network, comprising numerous glycan binding and/or modification enzymes or proteins that synthesize, transfer, sculpt and utilize N-linked glycans to direct folding vs. degradation, and trafficking of nascent N-glycoproteins through the cellular secretory pathway. If protein maturation is perturbed by misfolding and/or aggregation, stress pathways are often activated that result in transcriptional remodeling of the secretory pathway, in an attempt to alleviate the insult(s). The inability to achieve glycoproteostasis is linked to several pathologies, including amyloidoses, cystic fibrosis, and lysosomal storage diseases. Recent progress on genetic and pharmacologic adaptation of the glycoproteostasis network provides hope that drugs can be developed for these maladies in the near future.

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“…The cross-linking reaction was carried out as before with modification (41). Cells in 10-cm dishes were treated with 10 M proteasome inhibitor MG-132 for 2 h before harvesting.…”

Section: Methodsmentioning

confidence: 99%

Grp94 Protein Delivers γ-Aminobutyric Acid Type A (GABAA) Receptors to Hrd1 Protein-mediated Endoplasmic Reticulum-associated Degradation

Di¹,

Wang

Han³

et al. 2016

Journal of Biological Chemistry

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Proteostasis maintenance of ␥-aminobutyric acid type A (GABA A ) receptors dictates their function in controlling neuronal inhibition in mammalian central nervous systems. However, as a multisubunit, multispan, integral membrane protein, even wild type subunits of GABA A receptors fold and assemble inefficiently in the endoplasmic reticulum (ER). Unassembled and misfolded subunits undergo ER-associated degradation (ERAD), but this degradation process remains poorly understood for GABA A receptors. Here, using the ␣1 subunits of GABA A receptors as a model substrate, we demonstrated that Grp94, a metazoan-specific Hsp90 in the ER lumen, uses its middle domain to interact with the ␣1 subunits and positively regulates their ERAD. OS-9, an ER-resident lectin, acts downstream of Grp94 to further recognize misfolded ␣1 subunits in a glycan-dependent manner. This delivers misfolded ␣1 subunits to the Hrd1-mediated ubiquitination and the valosin-containing protein-mediated extraction pathway. Repressing the initial ERAD recognition step by inhibiting Grp94 enhances the functional surface expression of misfolding-prone ␣1(A322D) subunits, which causes autosomal dominant juvenile myoclonic epilepsy. This study clarifies a Grp94-mediated ERAD pathway for GABA A receptors, which provides a novel way to finely tune their function in physiological and pathophysiological conditions.

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FKBP10 Depletion Enhances Glucocerebrosidase Proteostasis in Gaucher Disease Fibroblasts

Cited by 16 publications

References 57 publications

ERdj3 Is an Endoplasmic Reticulum Degradation Factor for Mutant Glucocerebrosidase Variants Linked to Gaucher’s Disease

ERdj3 Is an Endoplasmic Reticulum Degradation Factor for Mutant Glucocerebrosidase Variants Linked to Gaucher’s Disease

The intrinsic and extrinsic effects of N-linked glycans on glycoproteostasis

Grp94 Protein Delivers γ-Aminobutyric Acid Type A (GABAA) Receptors to Hrd1 Protein-mediated Endoplasmic Reticulum-associated Degradation

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