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

ABSTRACT: Polarized vesicular trafficking directs specific receptors and ion channels to cilia, but the underlying mechanisms are poorly understood. Here we identify a key 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 caused ciliary elongation and cystogenesis, and cell-based proximity labelling proteomics and fluorescence microscopy showed alterations in the ciliary proteome upon loss of DLG1. Specifically, the retromer subunit SDCCAG3, IFT20 and polycystin-2 (PC2) were reduced in cilia of DLG1 deficient cells compared to control cells. This phenotype was recapitulated in vivo and rescuable by re-expression of wildtype DLG1, but not a Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)-associated DLG1 variant. Moreover, using biochemical approaches and Alpha Fold modelling we show that DLG1 associates physically with SDCCAG3 and IFT20, which in turn bind directly to each other. Our work identifies a key role for DLG1 in regulation ciliary protein composition and implicates ciliary dysfunction as a possible contributing factor to CAKUT.

SUBMITTER: Rezi CK 

PROVIDER: S-EPMC10659422 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature