Siah-1 interacts with the intracellular region of polycystin-1 and affects its stability via the ubiquitin-proteasome pathway.
Autosomal dominant polycystic kidney disease, characterized by extensive formation of renal cysts and progressive renal failure, is a genetic disorder caused by mutations in the PKD1 and PKD2 genes. The PKD1 gene product, polycystin-1, is a transmembrane protein with its N-terminus facing the extracellular region and C-terminus facing the cytoplasm. Polycystin-1 seems to be involved in regulating cell growth and maturation, but the precise mechanisms are not yet well defined. For investigating the function of the intracellular region of polycystin-1, the C-terminal cytoplasmic fragment of polycystin-1, PKD1-C, was used as bait in two-hybrid screening, and a polycystin-1-binding protein, the human homologue of Drosophila Seven in Absentia (Siah-1), which has a RING domain and promotes the ubiquitin-dependent proteasome pathway, was identified. It was shown that PKD1-C interacts with Siah-1 in vivo. In addition, interaction with Siah-1 induces the degradation of PKD1-C, shortening its half-life. PKD1-C and CD4 chimeric proteins, which are attached to the plasma membrane, also show similar results. Furthermore, ubiquitination and degradation of PKD1-C are increased in the presence of Siah-1, and overexpression of Siah-1 protein promotes the degradation of polycystin-1 via the ubiquitin-proteasome pathway. These results suggest that polycystin-1 is regulated by Siah-1 through the ubiquitin-dependent proteasome pathway.
Graduate School of Biotechnology, Korea University, Seoul 136-701, Korea.
Hyunho
H
Kim
Woocho
W
Jeong
Kwangseog
K
Ahn
Curie
C
Ahn
Seongman
S
Kang
D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050396:TRPP Cation Channels; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins
D003546:Cysteine Endopeptidases; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex; D011506:Proteins; D050396:TRPP Cation Channels; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins