DLG1 functions upstream of SDCCAG3 and IFT20 to control ciliary targeting of polycystin-2
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DLG1 functions upstream of SDCCAG3 and IFT20 to control ciliary targeting of polycystin-2. / Rezi, Csenge Kata; G. Aslanyan, Mariam ; D. Diwan, Gaurav ; Cheng, Tao; Chamlali, Mohamed; Junger, Katrin ; Anvarian, Zeinab; Lorentzen, Esben; Pauly, Kleo B.; Afshar-Bahadori, Yasmin; Alves Fernandes, Eduardo Felipe; Qian, Feng; Tosi, Sébastien; Christensen, Søren Tvorup; Pedersen, Stine Helene Falsig; Strømgaard, Kristian; B. Russell, Robert; H. Miner, Jeffrey; R. Mahjoub, Moe; Boldt, Karsten; Roepman, Ronald; Pedersen, Lotte Bang.
In: E M B O Reports, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - DLG1 functions upstream of SDCCAG3 and IFT20 to control ciliary targeting of polycystin-2
AU - Rezi, Csenge Kata
AU - G. Aslanyan, Mariam
AU - D. Diwan, Gaurav
AU - Cheng, Tao
AU - Chamlali, Mohamed
AU - Junger, Katrin
AU - Anvarian, Zeinab
AU - Lorentzen, Esben
AU - Pauly, Kleo B.
AU - Afshar-Bahadori, Yasmin
AU - Alves Fernandes, Eduardo Felipe
AU - Qian, Feng
AU - Tosi, Sébastien
AU - Christensen, Søren Tvorup
AU - Pedersen, Stine Helene Falsig
AU - Strømgaard, Kristian
AU - B. Russell, Robert
AU - H. Miner, Jeffrey
AU - R. Mahjoub, Moe
AU - Boldt, Karsten
AU - Roepman, Ronald
AU - Pedersen, Lotte Bang
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
U2 - 10.1038/s44319-024-00170-1
DO - 10.1038/s44319-024-00170-1
M3 - Journal article
C2 - 38849673
JO - E M B O Reports
JF - E M B O Reports
SN - 1469-221X
ER -
ID: 394431722