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

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 present details of clinical and molecular mechanisms of () loss-of-function.

Methods: This study was a systematic clinical and analysis of all published and newly identified cases using overexpression systems, patient fibroblasts, and mitogen-activated protein kinase binding protein 1 (MAPKBP1) knock down cells.

Results: We demonstrated that -NPH follows a distinct natural history, characterized by predominantly nonsyndromic kidney disease and exceptionally slow progression. Furthermore, we showed that endogenous MAPKBP1 is lost from ciliary basal bodies in patients with and in 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 Jun N-terminal kinase (JNK) determines the switch between centriolar association or dissociation of MAPKBP1 via distinct protein domains. Importantly, we found that JNK activation leads to the disassembly of cilia concomitantly with MAPKBP1 dissociation from the basal body. Downstream, we observed that impaired trafficking of phosphorylated JNK upon loss of MAPKBP1 and pharmacological disassembly of the JNK-target, actin, restores ciliary length in patients with . Overall, MAPKBP1-associated molecular alterations appeared to be relatively modest, in line with late onset kidney function decline in patients with .

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 are promising for the discovery of novel targets for urgently needed treatment strategies in NPH.