Galnt11 differential tissue glycoproteomics

ABSTRACT: Chronic kidney disease (CKD) affects more than 20 million Americans and approximately 10% of the population worldwide, and thus represents a major public health concern. Genome-wide association studies (GWAS) of kidney functional decline have identified genes associated with CKD, but the precise roles and mechanisms by which they influence kidney function remained largely unexplored. Here, we examine the role of one GWAS identified gene by creating mice deficient for Galnt11, which encodes a member of the enzyme family that initiates protein Oglycosylation, an essential post-translational 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, a1-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 Oglycosylation 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.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Liver, Kidney

SUBMITTER: Katrine Schjoldager  

LAB HEAD: Katrine Schjoldager

PROVIDER: PXD015429 | Pride | 2019-11-04

REPOSITORIES: Pride