TAZ promotes PC2 degradation through a SCFbeta-Trcp E3 ligase complex.
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 beta-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(beta-Trcp) E3 ubiquitin ligase pathway. Replacements of serines in a phosphodegron motif in TAZ prevent beta-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.
Tian
Yu
Y
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Kolb
Robert
R
Hong
Jeong-Ho
JH
Carroll
John
J
Li
Dawei
D
You
John
J
Bronson
Roderick
R
Yaffe
Michael B
MB
Zhou
Jing
J
Benjamin
Thomas
T
D000217:Acyltransferases; D000818:Animals; D002460:Cell Line; D044842:Cullin Proteins / Q000378:metabolism*; D044783:F-Box Proteins / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011233:Precipitin Tests; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D050396:TRPP Cation Channels / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism
D000217:Acyltransferases; D044842:Cullin Proteins; D044783:F-Box Proteins; D005982:Glutathione Transferase; D011506:Proteins; D011994:Recombinant Proteins; D044843:SKP Cullin F-Box Protein Ligases; D050396:TRPP Cation Channels; D014157:Transcription Factors; D014452:Ubiquitins; C486363:tafazzin protein, mouse