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Galnt11 regulates kidney function by glycosylating the endocytosis receptor megalin to modulate ligand binding

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Tian, E ; Wang, Shengjun ; Zhang, Liping ; Zhang, Ying ; Malicdan, May C ; Mao, Yang ; Christoffersen, Christina ; Tabak, Lawrence A ; Schjoldager, Katrine T ; Ten Hagen, Kelly G. / Galnt11 regulates kidney function by glycosylating the endocytosis receptor megalin to modulate ligand binding. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 50. pp. 25196-25202.

Bibtex

@article{94fd2d8fd05541269282d620bc23c33b,
title = "Galnt11 regulates kidney function by glycosylating the endocytosis receptor megalin to modulate ligand binding",
abstract = "Chronic kidney disease (CKD) affects more than 20 million Americans and ∼10{\%} of the population worldwide. Genome-wide association studies (GWAS) of kidney functional decline have identified genes associated with CKD, but the precise mechanisms by which they influence kidney function remained largely unexplored. Here, we examine the role of 1 GWAS-identified gene by creating mice deficient for Galnt11, which encodes a member of the enzyme family that initiates protein O-glycosylation, an essential posttranslational modification known to influence protein function and stability. We find that Galnt11-deficient mice display low-molecular-weight proteinuria and have specific defects in proximal tubule-mediated resorption of vitamin D binding protein, α1-microglobulin, and retinol binding protein. Moreover, we identify the endocytic receptor megalin (LRP2) as a direct target of Galnt11 in vivo. Megalin in Galnt11-deficient mice displays reduced ligand binding and undergoes age-related loss within the kidney. Differential mass spectrometry revealed specific sites of Galnt11-mediated glycosylation within mouse kidney megalin/LRP2 that are known to be involved in ligand binding, suggesting that O-glycosylation directly influences the ability to bind ligands. In support of this, recombinant megalin containing these sites displayed reduced albumin binding in cells deficient for Galnt11 Our results provide insight into the association between GALNT11 and CKD, and identify a role for Galnt11 in proper kidney function.",
author = "E Tian and Shengjun Wang and Liping Zhang and Ying Zhang and Malicdan, {May C} and Yang Mao and Christina Christoffersen and Tabak, {Lawrence A} and Schjoldager, {Katrine T} and {Ten Hagen}, {Kelly G}",
year = "2019",
month = "12",
day = "10",
doi = "10.1073/pnas.1909573116",
language = "English",
volume = "116",
pages = "25196--25202",
journal = "National Academy of Sciences. Proceedings",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "50",

}

RIS

TY - JOUR

T1 - Galnt11 regulates kidney function by glycosylating the endocytosis receptor megalin to modulate ligand binding

AU - Tian, E

AU - Wang, Shengjun

AU - Zhang, Liping

AU - Zhang, Ying

AU - Malicdan, May C

AU - Mao, Yang

AU - Christoffersen, Christina

AU - Tabak, Lawrence A

AU - Schjoldager, Katrine T

AU - Ten Hagen, Kelly G

PY - 2019/12/10

Y1 - 2019/12/10

N2 - Chronic kidney disease (CKD) affects more than 20 million Americans and ∼10% of the population worldwide. Genome-wide association studies (GWAS) of kidney functional decline have identified genes associated with CKD, but the precise mechanisms by which they influence kidney function remained largely unexplored. Here, we examine the role of 1 GWAS-identified gene by creating mice deficient for Galnt11, which encodes a member of the enzyme family that initiates protein O-glycosylation, an essential posttranslational modification known to influence protein function and stability. We find that Galnt11-deficient mice display low-molecular-weight proteinuria and have specific defects in proximal tubule-mediated resorption of vitamin D binding protein, α1-microglobulin, and retinol binding protein. Moreover, we identify the endocytic receptor megalin (LRP2) as a direct target of Galnt11 in vivo. Megalin in Galnt11-deficient mice displays reduced ligand binding and undergoes age-related loss within the kidney. Differential mass spectrometry revealed specific sites of Galnt11-mediated glycosylation within mouse kidney megalin/LRP2 that are known to be involved in ligand binding, suggesting that O-glycosylation directly influences the ability to bind ligands. In support of this, recombinant megalin containing these sites displayed reduced albumin binding in cells deficient for Galnt11 Our results provide insight into the association between GALNT11 and CKD, and identify a role for Galnt11 in proper kidney function.

AB - Chronic kidney disease (CKD) affects more than 20 million Americans and ∼10% of the population worldwide. Genome-wide association studies (GWAS) of kidney functional decline have identified genes associated with CKD, but the precise mechanisms by which they influence kidney function remained largely unexplored. Here, we examine the role of 1 GWAS-identified gene by creating mice deficient for Galnt11, which encodes a member of the enzyme family that initiates protein O-glycosylation, an essential posttranslational modification known to influence protein function and stability. We find that Galnt11-deficient mice display low-molecular-weight proteinuria and have specific defects in proximal tubule-mediated resorption of vitamin D binding protein, α1-microglobulin, and retinol binding protein. Moreover, we identify the endocytic receptor megalin (LRP2) as a direct target of Galnt11 in vivo. Megalin in Galnt11-deficient mice displays reduced ligand binding and undergoes age-related loss within the kidney. Differential mass spectrometry revealed specific sites of Galnt11-mediated glycosylation within mouse kidney megalin/LRP2 that are known to be involved in ligand binding, suggesting that O-glycosylation directly influences the ability to bind ligands. In support of this, recombinant megalin containing these sites displayed reduced albumin binding in cells deficient for Galnt11 Our results provide insight into the association between GALNT11 and CKD, and identify a role for Galnt11 in proper kidney function.

U2 - 10.1073/pnas.1909573116

DO - 10.1073/pnas.1909573116

M3 - Journal article

VL - 116

SP - 25196

EP - 25202

JO - National Academy of Sciences. Proceedings

JF - National Academy of Sciences. Proceedings

SN - 0027-8424

IS - 50

ER -

ID: 58645819