Galnt11 regulates kidney function by glycosylating the endocytosis receptor megalin to modulate ligand binding
| Autor: | Shengjun Wang, May Christine V. Malicdan, Ying Zhang, Kelly G. Ten Hagen, Liping Zhang, Christina Christoffersen, Katrine T. Schjoldager, Lawrence A. Tabak, E Tian, Yang Mao |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Glycosylation Vitamin D-binding protein Endocytic cycle Population Kidney Ligands urologic and male genital diseases Kidney Tubules Proximal Mice 03 medical and health sciences 0302 clinical medicine Alpha-Globulins medicine Animals Humans Renal Insufficiency Chronic education Receptor Mice Knockout education.field_of_study Multidisciplinary Chemistry Vitamin D-Binding Protein Biological Sciences LRP2 medicine.disease Endocytosis Cell biology Low Density Lipoprotein Receptor-Related Protein-2 Retinol binding protein 030104 developmental biology medicine.anatomical_structure N-Acetylgalactosaminyltransferases Female 030217 neurology & neurosurgery Protein Binding Kidney disease |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1909573116 |
| Popis: | 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, α 1 -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. |
| Databáze: | OpenAIRE |
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