DLG1 functions upstream of SDCCAG3 and IFT20 to control targeting of polycystin-2 to the primary cilium

Rezi, C. K.; Aslanyan, M.; Diwan, G. D.; Cheng, T.; Chamlali, M.; Junger, K.; Anvarian, Z.; Lorentzen, E.; Pauly, K. B.; Bahadori, Y.; Fernandes, E. F.; Qian, F.; Tosi, S.; Christensen, S. T.; Pedersen, S. F.; Stromgaard, K.; Russell, R. B.; Miner, J. H.; Mahjoub, M. R.; Boldt, K.; Roepman, R.; Pedersen, L. B.

doi:10.1101/2023.11.10.566524

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bioRxiv · 10.1101/2023.11.10.566524

DLG1 functions upstream of SDCCAG3 and IFT20 to control targeting of polycystin-2 to the primary cilium

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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 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-associated protein 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, p.T489R. Finally, biochemical approaches and Alpha Fold modelling suggested 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.

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Rezi, C. K., Aslanyan, M., Diwan, G. D., Cheng, T., Chamlali, M., Junger, K., Anvarian, Z., Lorentzen, E., Pauly, K. B., Bahadori, Y., Fernandes, E. F., Qian, F., Tosi, S., Christensen, S. T., Pedersen, S. F., Stromgaard, K., Russell, R. B., Miner, J. H., Mahjoub, M. R., Boldt, K., Roepman, R., Pedersen, L. B.. 2023-11-10. DLG1 functions upstream of SDCCAG3 and IFT20 to control targeting of polycystin-2 to the primary cilium. https://doi.org/10.1101/2023.11.10.566524

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