Borgal, L., Habbig, S., Hatzold, J., Liebau, M.C., Dafinger, C., Sacarea, I., Hammerschmidt, M., Benzing, T., and Schermer, B. (2012) The Ciliary Protein Nephrocystin-4 Translocates the Canonical Wnt-Regulator Jade-1 to the Nucleus to Negatively Regulate Beta-Catenin Signaling. The Journal of biological chemistry. 287(30):25370-25380.
Nephronophthisis (NPH) is an autosomal-recessive cystic kidney disease and represents the most common genetic cause for endstage
renal disease in children and adolescents. It can be caused by mutation of genes encoding for the nephrocystin proteins (NPHPs).
All NPHPs localize to primary cilia, classifying this disease as a 'ciliopathy'. The primary cilium is a critical regulator
of several cell signaling pathways. Cystogenesis in the kidney is thought to involve over-activation of canonical Wnt signaling,
which is negatively regulated by the primary cilium and several NPH proteins, although the mechanism remains unclear. Jade-1
has recently been identified as a novel ubiquitin ligase targeting the canonical Wnt downstream effector beta-catenin for
proteasomal degradation. Here, we identify Jade-1 as a novel component of the NPHP protein complex: Jade-1 colocalizes with
NPHP1 at the transition zone of primary cilia, and interacts with NPHP4. Furthermore, NPHP4 stabilizes protein levels of Jade-1
and promotes the translocation of Jade-1 to the nucleus. Finally, NPHP4 and Jade-1 additively inhibit canonical Wnt signaling,
and this genetic interaction is conserved in zebrafish. The stabilization and nuclear translocation of Jade-1 by NPHP4 enhances
the ability of Jade-1 to negatively regulate canonical Wnt signaling. Loss of this repressor function in Nephronophthisis
might be an important factor promoting Wnt activation and contributing to cyst formation.