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

E Tian; Shengjun Wang; Liping Zhang; Ying Zhang; May C Malicdan; Yang Mao; Christina Christoffersen; Lawrence A Tabak; Katrine T Schjoldager; Kelly G Ten Hagen

doi:10.1073/pnas.1909573116

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

E Tian, Shengjun Wang, Liping Zhang, Ying Zhang, May C Malicdan, Yang Mao, Christina Christoffersen, Lawrence A Tabak, Katrine T Schjoldager, Kelly G Ten Hagen

11 Citations (Scopus)

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.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	50
Pages (from-to)	25196-25202
Number of pages	7
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1909573116
Publication status	Published - 10 Dec 2019

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Tian, E., Wang, S., Zhang, L., Zhang, Y., Malicdan, M. C., Mao, Y., Christoffersen, C., Tabak, L. A., Schjoldager, K. T., & Ten Hagen, K. G. (2019). Galnt11 regulates kidney function by glycosylating the endocytosis receptor megalin to modulate ligand binding. Proceedings of the National Academy of Sciences of the United States of America, 116(50), 25196-25202. https://doi.org/10.1073/pnas.1909573116

Galnt11 regulates kidney function by glycosylating the endocytosis receptor megalin to modulate ligand binding. / Tian, E; Wang, Shengjun; Zhang, Liping et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 50, 10.12.2019, p. 25196-25202.

Research output: Contribution to journal › Journal article › Research › peer-review

Tian, E, Wang, S, Zhang, L, Zhang, Y, Malicdan, MC, Mao, Y, Christoffersen, C, Tabak, LA, Schjoldager, KT & Ten Hagen, KG 2019, 'Galnt11 regulates kidney function by glycosylating the endocytosis receptor megalin to modulate ligand binding', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 50, pp. 25196-25202. https://doi.org/10.1073/pnas.1909573116

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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.",

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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

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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.

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

Abstract

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