Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus
Veronique Chauvet, Xin Tian, Herve Husson, David H. Grimm, Tong Wang, Thomas Hieseberger, Peter Igarashi, Anton M. Bennett, Oxana Ibraghimov-Beskrovnaya, Stefan Somlo, Michael J. Caplan
Veronique Chauvet, Xin Tian, Herve Husson, David H. Grimm, Tong Wang, Thomas Hieseberger, Peter Igarashi, Anton M. Bennett, Oxana Ibraghimov-Beskrovnaya, Stefan Somlo, Michael J. Caplan
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Article Nephrology

Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus

Abstract

Polycystin-1, which is encoded by a gene that is mutated in autosomal dominant polycystic kidney disease (ADPKD), is involved in cell-matrix interactions as well as in ciliary signaling. The precise mechanisms by which it functions, however, remain unclear. Here we find that polycystin-1 undergoes a proteolytic cleavage that releases its C-terminal tail (CTT), which enters the nucleus and initiates signaling processes. The cleavage occurs in vivo in association with alterations in mechanical stimuli. Polycystin-2, the product of the second gene mutated in ADPKD, modulates the signaling properties of the polycystin-1 CTT. These data reveal a novel pathway by which polycystin-1 transmits messages directly to the nucleus.

Authors

Veronique Chauvet, Xin Tian, Herve Husson, David H. Grimm, Tong Wang, Thomas Hieseberger, Peter Igarashi, Anton M. Bennett, Oxana Ibraghimov-Beskrovnaya, Stefan Somlo, Michael J. Caplan

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The CTT of polycystin-1 is detected in the nuclei of epithelial cells of...
The CTT of polycystin-1 is detected in the nuclei of epithelial cells of developing kidneys in WT mouse embryos at 13 days after conception. (A–L) Abundant polycystin-1 staining is detected with Mex-46–AP in the condensing metanephric mesenchyme (S, S body) and developing tubules (T) of WT mouse embryos (A–C and G–I) but not in the developing kidneys of polycystin-1 KO mice (D–F and J–L). The regions outlined in the boxes in panels A–F (original magnification, ×200) are shown at higher magnification in panels G–L (original magnification, ×750). Nuclear staining (arrows) is present in developing tubules of WT embryos (A and G). The Mex-46–AP signal appears to be excluded from nucleoli (dark arrowheads in G). Nuclei are visualized through staining with Hoechst 33342 (B, E, H, and K), and superposition of antibody (red) and nuclear (blue) staining is depicted in panels C, F, I, and L (Overlay).