Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus
Veronique Chauvet, … , Stefan Somlo, Michael J. Caplan
Veronique Chauvet, … , Stefan Somlo, Michael J. Caplan
Published November 15, 2004
Citation Information: J Clin Invest. 2004;114(10):1433-1443. https://doi.org/10.1172/JCI21753.
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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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Figure 5

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Influence of polycystin-2 expression. (A) When coexpressed in Cos-7 cell...
Influence of polycystin-2 expression. (A) When coexpressed in Cos-7 cells with full-length polycystin-2 (red), p-200 (green) is excluded from the nucleus and localizes instead to intracellular membranes whose distribution resembles that of the ER. (B) Coexpression of polycystin-2 with p200 decreases the AP-1 activation induced by p200 by a factor of about 2.5 (top). The level of expression of the p200 and pc-2 constructs was determined by Western blotting (bottom). Polycystin-2Ø (pc-2Ø) refers to a construct that lacks the domain of polycystin-2 that interacts with polycystin-1. (C–H) The CTT of polycystin-1 (stained with Mex-46; C and F) is detected in the nuclei of renal tubular epithelial cells from mice expressing a reduced level of polycystin-2 (C–E, Pkd2+/–; F–H, Pkd2WS25/–); nuclei were detected with Hoechst 33342 (D and G). (E and H) Superposition of Hoechst (blue) and Mex-46 (red) staining. Original magnifications, ×100 (A) and ×750 (C–H).