DLG1 functions upstream of SDCCAG3 and IFT20 to control ciliary targeting of polycystin-2

EMBO Rep. 2024 Jul;25(7):3040-3063. doi: 10.1038/s44319-024-00170-1. Epub 2024 Jun 7.


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.

Keywords: DLG1; IFT20; Polycystin-2; Primary Cilia; SDCCAG3.

MeSH terms

  • Animals
  • Carrier Proteins* / genetics
  • Carrier Proteins* / metabolism
  • Cilia* / metabolism
  • Discs Large Homolog 1 Protein* / metabolism
  • Epithelial Cells / metabolism
  • Humans
  • Kidney / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Protein Binding
  • Protein Transport
  • TRPP Cation Channels* / genetics
  • TRPP Cation Channels* / metabolism
  • Urogenital Abnormalities
  • Vesico-Ureteral Reflux / genetics
  • Vesico-Ureteral Reflux / metabolism


  • TRPP Cation Channels
  • Discs Large Homolog 1 Protein
  • polycystic kidney disease 2 protein
  • Carrier Proteins
  • Dlg1 protein, mouse
  • Ift20 protein, mouse
  • Membrane Proteins

Supplementary concepts

  • Cakut