1. DLG1 functions upstream of SDCCAG3 and IFT20 to control ciliary targeting of polycystin-2.
- Author
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Rezi CK, Aslanyan MG, Diwan GD, Cheng T, Chamlali M, Junger K, Anvarian Z, Lorentzen E, Pauly KB, Afshar-Bahadori Y, Fernandes EF, Qian F, Tosi S, Christensen ST, Pedersen SF, Strømgaard K, Russell RB, Miner JH, Mahjoub MR, Boldt K, Roepman R, and Pedersen LB
- Subjects
- Animals, Mice, Humans, Protein Transport, Mice, Knockout, Kidney metabolism, Epithelial Cells metabolism, Protein Binding, Vesico-Ureteral Reflux metabolism, Vesico-Ureteral Reflux genetics, Membrane Proteins metabolism, Membrane Proteins genetics, Urogenital Abnormalities, Cilia metabolism, TRPP Cation Channels metabolism, TRPP Cation Channels genetics, Discs Large Homolog 1 Protein metabolism, Carrier Proteins metabolism, Carrier Proteins genetics
- Abstract
Polarized vesicular trafficking directs specific receptors and ion channels to cilia, but the underlying mechanisms are poorly understood. Here we describe a role for DLG1, a core component of the Scribble polarity complex, in regulating ciliary protein trafficking in kidney epithelial cells. Conditional knockout of Dlg1 in mouse kidney causes ciliary elongation and cystogenesis, and cell-based proximity labeling proteomics and fluorescence microscopy show alterations in the ciliary proteome upon loss of DLG1. Specifically, the retromer-associated protein SDCCAG3, IFT20, and polycystin-2 (PC2) are reduced in the cilia of DLG1-deficient cells compared to control cells. This phenotype is recapitulated in vivo and rescuable by re-expression of wild-type DLG1, but not a Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)-associated DLG1 variant, p.T489R. Finally, biochemical approaches and Alpha Fold modelling suggest that SDCCAG3 and IFT20 form a complex that associates, at least indirectly, with DLG1. Our work identifies a key role for DLG1 in regulating ciliary protein composition and suggests that ciliary dysfunction of the p.T489R DLG1 variant may contribute to CAKUT., (© 2024. The Author(s).)
- Published
- 2024
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