KLC3 Regulates Ciliary Trafficking and Cyst Progression in CILK1 Deficiency–Related Polycystic Kidney Disease. Issue 9 (September 2022) - Rah, Gyuyeong
Significance Statement: Mutations in ciliogenesis-associated kinase 1 ( CILK1 ) cause ciliopathies. However, the pathogenesis of the ciliary defect in the CILK1-deficient kidney remains unknown. We found that CILK1 deficiency in a mouse model leads to polycystic kidney disease (PKD) with abnormal ciliary trafficking and that kinesin light chain–3 (KLC3), a novel ciliary regulator, interacts with CILK1. Furthermore, KLC3 localizes at cilia bases, where it promotes ciliary trafficking of the IFT-EGFR complex, which contributes to cyst progression. KLC3 knockdown restored abnormal ciliary trafficking and cyst progression caused by CILK1 deficiency. Identifying KLC3 as a ciliary regulator involved in cystogenesis provides insights into the pathogenesis of CILK1 deficiency–related PKD. Visual Abstract: Abstract : Background: Ciliogenesis-associated kinase 1 ( CILK1 ) is a ciliary gene that localizes in primary cilia and regulates ciliary transport. Mutations in CILK1 cause various ciliopathies. However, the pathogenesis of CILK1-deficient kidney disease is unknown. Methods: To examine whether CILK1 deficiency causes PKD accompanied by abnormal cilia, we generated mice with deletion of Cilk1 in cells of the renal collecting duct. A yeast two-hybrid system and coimmunoprecipitation (co-IP) were used to identify a novel regulator, kinesin light chain–3 (KLC3), of ciliary trafficking and cyst progression in the Cilk1 -deficient model. Immunocytochemistry and co-IP were used to examine the effect of KLC3 on ciliary trafficking of the IFT-B complex and EGFR. We evaluated the effects of these genes on ciliary trafficking and cyst progression by modulating CILK1 and KLC3 expression levels. Results: CILK1 deficiency leads to PKD accompanied by abnormal ciliary trafficking. KLC3 interacts with CILK1 at cilia bases and is increased in cyst-lining cells of CILK1-deficient mice. KLC3 overexpression promotes ciliary recruitment of IFT-B and EGFR in the CILK1 deficiency condition, which contributes to the ciliary defect in cystogenesis. Reduction in KLC3 rescued the ciliary defects and inhibited cyst progression caused by CILK1 deficiency. Conclusions: Our findings suggest that CILK1 deficiency in renal collecting ducts leads to PKD and promotes ciliary trafficking via increased KLC3.