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

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. Condit...

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Main Authors: Rezi, Csenge K. (Author) , Aslanyan, Mariam G (Author) , Diwan, Gaurav (Author) , Cheng, Tao (Author) , Chamlali, Mohamed (Author) , Junger, Katrin (Author) , Anvarian, Zeinab (Author) , Lorentzen, Esben (Author) , Pauly, Kleo B (Author) , Afshar-Bahadori, Yasmin (Author) , Fernandes, Eduardo FA (Author) , Qian, Feng (Author) , Tosi, Sébastien (Author) , Christensen, Søren T (Author) , Pedersen, Stine F (Author) , Strømgaard, Kristian (Author) , Russell, Robert B. (Author) , Miner, Jeffrey H (Author) , Mahjoub, Moe R (Author) , Boldt, Karsten (Author) , Roepman, Ronald (Author) , Pedersen, Lotte B (Author)
Format: Article (Journal)
Language:English
Published: 7 June 2024
In: EMBO reports
Year: 2024, Volume: 25, Issue: 7, Pages: 3040-3063
ISSN:1469-3178
DOI:10.1038/s44319-024-00170-1
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s44319-024-00170-1
Verlag, kostenfrei, Volltext: https://www.embopress.org/doi/full/10.1038/s44319-024-00170-1
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Author Notes:Csenge K Rezi, Mariam G Aslanyan, Gaurav D Diwan, Tao Cheng, Mohamed Chamlali, Katrin Junger, Zeinab Anvarian, Esben Lorentzen, Kleo B Pauly, Yasmin Afshar-Bahadori, Eduardo FA Fernandes, Feng Qian, Sébastien Tosi, Søren T Christensen, Stine F Pedersen, Kristian Strømgaard, Robert B Russell, Jeffrey H Miner, Moe R Mahjoub, Karsten Boldt, Ronald Roepman & Lotte B Pedersen
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Summary: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.
Item Description:Gesehen am 24.01.2025
Physical Description:Online Resource
ISSN:1469-3178
DOI:10.1038/s44319-024-00170-1

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