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

Proc Natl Acad Sci U S A. 2019 Dec 10;116(50):25196-25202. Epub 2019 Nov 18
E Tian 1 , Shengjun Wang 2 , Liping Zhang 1 , Ying Zhang 3 , May C Malicdan 4 , Yang Mao 2 , Christina Christoffersen 5 , Lawrence A Tabak 6 , Katrine T Schjoldager 7 , Kelly G Ten Hagen 8
E Tian 1 , Shengjun Wang 2 , Liping Zhang 1 , Ying Zhang 3 , May C Malicdan 4 , Yang Mao 2 , Christina Christoffersen 5 , Lawrence A Tabak 6 , Katrine T Schjoldager 7 , Kelly G Ten Hagen 8
+ et al

[No authors listed]

Author information
  • 1 Developmental Glycobiology Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, MD 20892-4370.
  • 2 School of Pharmaceutical Sciences, Sun Yat-sen University, 510006 Guangzhou, China.
  • 3 Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908.
  • 4 Undiagnosed Diseases Program, Office of the Clinical Director, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, MD 20892.
  • 5 Department of Biomedical Sciences, Rigshospitalet, University of Copenhagen, 2200 Copenhagen, Denmark.
  • 6 Section on Biological Chemistry, NIDCR, National Institutes of Health, Bethesda, MD 20892-4370.
  • 7 Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
  • 8 Developmental Glycobiology Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, MD 20892-4370; Kelly.Tenhagen@nih.gov.

摘要


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.

KEYWORDS: GALNT11, O-glycosylation, kidney disease, megalin, proteinuria