194 N-Glycosylation Is Essential for Ileal ASBT Function and Protection Against Proteases

Muthusamy, Saminathan; Malhotra, P.K.; Hosameddin, Mobashir; Dudeja, Amish K.; Borthakur, Sujata; Saksena, Seema; Gill, Ravinder K.; Dudeja, Pradeep K.; Alrefai, Waddah A.

doi:10.1016/s0016-5085(14)60177-3

Cited by 2 publications

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“…Regulation of bile acid homeostasis through the FXR-Fgf15 pathway is a primary role of the ileal epithelium, and uptake of bile acids has been shown to be dependent on N-glycosylation. 41 We have previously shown that carriers of ZIP8 391-Thr with Crohn's disease have a distinct ileal and rectal mucosal microbiota profile associated with aberrant bile acid homeostasis. 42 Further, in a subset of patients with ileocolonic Crohn's disease, ZIP8 391-Thr carriers had decreased circulating FGF19 levels.…”

Section: Defects In Bile Acid Homeostasis and Intestinal Permeability...mentioning

confidence: 99%

Aberrant N-glycosylation is a therapeutic target in carriers of a common and highly pleiotropic mutation in the manganese transporter ZIP8

Tomar,

Kang,

Lin

et al. 2024

Preprint

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The treatment of defective glycosylation in clinical practice has been limited to patients with rare and severe phenotypes associated with congenital disorders of glycosylation (CDG). Carried by approximately 5% of the human population, the discovery of the highly pleiotropic, missense mutation in a manganese transporter ZIP8 has exposed under-appreciated roles for Mn homeostasis and aberrant Mn-dependent glycosyltransferases activity leading to defective N-glycosylation in complex human diseases. Here, we test the hypothesis that aberrant N-glycosylation contributes to disease pathogenesis of ZIP8 A391T-associated Crohn’s disease. Analysis of N-glycan branching in intestinal biopsies demonstrates perturbation in active Crohn’s disease and a genotype-dependent effect characterized by increased truncated N-glycans. A mouse model of ZIP8 391-Thr recapitulates the intestinal glycophenotype of patients carrying mutations in ZIP8. Borrowing from therapeutic strategies employed in the treatment of patients with CDGs, oral monosaccharide therapy with N-acetylglucosamine ameliorates the epithelial N-glycan defect, bile acid dyshomeostasis, intestinal permeability, and susceptibility to chemical-induced colitis in a mouse model of ZIP8 391-Thr. Together, these data support ZIP8 391-Thr alters N-glycosylation to contribute to disease pathogenesis, challenging the clinical paradigm that CDGs are limited to patients with rare diseases. Critically, the defect in glycosylation can be targeted with monosaccharide supplementation, providing an opportunity for genotype-driven, personalized medicine.

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Section: Defects In Bile Acid Homeostasis and Intestinal Permeability...mentioning

confidence: 99%

Aberrant N-glycosylation is a therapeutic target in carriers of a common and highly pleiotropic mutation in the manganese transporter ZIP8

Tomar,

Kang,

Lin

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…23−29 However, there is limited information about the post-transcriptional and post-translational regulation of hASBT. Recently, Alrefai and colleagues 30 partly delineated the role of N-linked glycosylation in the regulation of hASBT protein and in its role as a protective mechanism against protease degradation. Additionally, Xia and colleagues 31 showed ubiquitin−proteasome-dependent degradation of rat Asbt through a process involving JNK-mediated serine/ threonine phosphorylation, followed by independent studies reporting the short-term regulation of hASBT by various kinases such as PKC, PKA, and MAP kinases.…”

Section: ■ Introductionmentioning

confidence: 99%

Tyrosine Phosphorylation Regulates Plasma Membrane Expression and Stability of the Human Bile Acid Transporter ASBT (SLC10A2)

et al. 2019

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The human apical sodium-dependent bile acid transporter (hASBT; SLC10A2) is responsible for the reclamation of bile acids from the intestinal lumen, providing a primary mechanism for bile acid and cholesterol homeostasis. However, the regulation of hASBT at the post-translational level is not well understood. In the present study, we investigated the role of Src family kinases (SFKs) and protein tyrosine phosphatases (PTPs) in the regulation of surface expression and function of hASBT. Inhibition of Src family kinases, via treatment with PP2, significantly reduced hASBT function, while the inhibition of PTPs by activated orthovanadate significantly induced function. Src family kinase inhibition by PP2 was associated with a concomitant decrease in maximum transport velocity (J max ) correlated with a decrease in hASBT surface expression. Interestingly, PP2-mediated suppression of hASBT protein expression was rescued by the proteasome inhibitor MG132, suggesting that dephosphorylation impacts protein stability with the subsequent proteasomedependent degradation of hASBT. Consequently, single-point mutations were introduced at five intracellular tyrosine residues: Y148F, Y216F, Y308F, Y311F, and Y337F. Although all mutants had significantly altered hASBT function without changes in total cellular expression, sequential tyrosine mutations at the five residues above rendered hASBT nonfunctional with diminished protein expression. Furthermore, orthovanadate-induced transport activity of single-point tyrosine mutants suggested a role for multiple tyrosine residues in the regulation of hASBT function and membrane expression. Overall, our data confirms that tyrosine phosphorylation mediated by Src family kinases (SFKs), in particular, regulates surface expression, function, and stability of hASBT.

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194 N-Glycosylation Is Essential for Ileal ASBT Function and Protection Against Proteases

Cited by 2 publications

References 0 publications

Aberrant N-glycosylation is a therapeutic target in carriers of a common and highly pleiotropic mutation in the manganese transporter ZIP8

Aberrant N-glycosylation is a therapeutic target in carriers of a common and highly pleiotropic mutation in the manganese transporter ZIP8

Tyrosine Phosphorylation Regulates Plasma Membrane Expression and Stability of the Human Bile Acid Transporter ASBT (SLC10A2)

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