TAZ Promotes PC2 Degradation through a SCF^β-Trcp E3 Ligase Complex

Abstract

Studies of a TAZ knockout mouse reveal a novel function of the transcriptional regulator TAZ, that is, as a binding partner of the F-box protein β-Trcp. TAZ^−/− mice develop polycystic kidney disease (PKD) and emphysema. The calcium-permeable cation channel protein polycystin 2 (PC2) is overexpressed in kidneys of TAZ^−/− mice as a result of decreased degradation via an SCF^β-Trcp E3 ubiquitin ligase pathway. Replacements of serines in a phosphodegron motif in TAZ prevent β-Trcp binding and PC2 degradation. Coexpression of a cytoplasmic fragment of polycystin 1 blocks the PC2-TAZ interaction and prevents TAZ-mediated degradation of PC2. Depletion of TAZ in zebrafish also results in a cystic kidney accompanied by overexpression of PC2. These results establish a common role of TAZ across vertebrate species in a protein degradation pathway regulated by phosphorylation and implicate deficiencies in this pathway in the development of PKD.

SUPPLEMENTAL MATERIAL

This work has been supported by grants from the National Cancer Institute, RO1 CA92520 and CA 90992 to T.B., NIH grant GM60594 to M.Y., grants RO1DK53357, RO1DK40703, and RO1DK51050 to J.Z., and by fellowship 70a2f from the Polycystic Kidney Disease Foundation to Y.T.

We gratefully acknowledge Armin Arnaout, Adam Amsterdam, and Wade Harper for helpful discussions and Wade Harper, Haihua Gu, and Gerd Walz for providing reagents. Services of the Transgenic Mouse Facility of the Brigham and Women's Hospital and the Rodent Histopathology Core of the Dana Farber-Harvard Cancer Center are also gratefully acknowledged.