Back to Search
Start Over
The ciliary protein nephrocystin-4 translocates the canonical Wnt regulator Jade-1 to the nucleus to negatively regulate β-catenin signaling.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2012 Jul 20; Vol. 287 (30), pp. 25370-80. Date of Electronic Publication: 2012 May 31. - Publication Year :
- 2012
-
Abstract
- 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.
- Subjects :
- Active Transport, Cell Nucleus genetics
Adolescent
Animals
Cell Nucleus genetics
Child
Child, Preschool
HEK293 Cells
Homeodomain Proteins genetics
Humans
Kidney Diseases, Cystic congenital
Kidney Diseases, Cystic genetics
Kidney Diseases, Cystic metabolism
Male
Proteins genetics
Tumor Suppressor Proteins genetics
Zebrafish genetics
Zebrafish Proteins genetics
beta Catenin genetics
Cell Nucleus metabolism
Homeodomain Proteins metabolism
Proteins metabolism
Tumor Suppressor Proteins metabolism
Wnt Signaling Pathway
Zebrafish metabolism
Zebrafish Proteins metabolism
beta Catenin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 287
- Issue :
- 30
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22654112
- Full Text :
- https://doi.org/10.1074/jbc.M112.385658