Structure-Activity Analysis Reveals Perturbed Cilia-Jun N-Terminal Kinase Signaling in MAPKBP1-Associated Kidney Disease

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Introduction Nephronophthisis (NPH) is a renal ciliopathy characterized by chronic tubulointerstitial fibrosis. Despite discovery of multiple disease genes, mechanisms of NPH-associated kidney degeneration remain poorly understood. In this study, we detail clinical and molecular mechanisms of MAPKBP1 ( NPHP20 ) loss-of-function. Methods Systematic clinical and in vitro analysis of all published and newly identified cases using overexpression systems, patient fibroblasts, and MAPKBP1 knock down cells. Results We demonstrate that MAPKBP1 -NPH follows a distinct natural history, characterized by predominantly non-syndromic kidney disease and exceptionally slow progression. Furthermore, we show that endogenous MAPKBP1 is lost from ciliary basal bodies in NPHP20 patients and MAPKBP1 knock down, accompanied by shortened primary cilia. Overexpression of MAPKBP1 patient variants revealed impaired microtubule, centrosomal, and basal body localization. We propose that the activation status of JNK determines the switch between centriolar association or dissociation of MAPKBP1 via distinct protein domains. Importantly, we find that JNK activation leads to the disassembly of cilia concomitantly with MAPKBP1 dissociation from the basal body. Downstream, we observe impaired trafficking of phosphorylated JNK upon loss of MAPKBP1 and pharmacological disassembly of the JNK-target actin restores ciliary length in NPHP20 patients. Overall, MAPKBP1-associated molecular alterations appear to be relatively modest, in line with late onset kidney function decline in NPHP20 patients. Conclusion In summary, we propose alterations in cilia-related JNK pathways as a novel mechanism in the development of NPH. Thus, a more detailed investigation of JNK signaling and involved protein interactions promises discovery of novel targets for urgently needed treatment strategies in NPH.

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