The ciliary protein nephrocystin-4 translocates the canonical Wnt regulator Jade-1 to the nucleus to negatively regulate β-catenin signaling.
Nephronophthisis (NPH) is an autosomal-recessive cystic kidney disease and represents the most common genetic cause for end-stage renal disease in children and adolescents. It can be caused by the 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 overactivation 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 β-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.
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, 50937 Cologne, Germany.
Lori
L
Borgal
Sandra
S
Habbig
Julia
J
Hatzold
Max C
MC
Liebau
Claudia
C
Dafinger
Ilinca
I
Sacarea
Matthias
M
Hammerschmidt
Thomas
T
Benzing
Bernhard
B
Schermer
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000293:Adolescent; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000151:congenital / Q000235:genetics / Q000378:metabolism; D008297:Male; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D018398:Homeodomain Proteins; C469360:JADE1 protein, human; C491578:NPHP4 protein, human; D011506:Proteins; D025521:Tumor Suppressor Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C561793:nephrocystin-4, zebrafish