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Human Molecular Genetics 2007 16(8):942-956; doi:10.1093/hmg/ddm039
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Polyductin undergoes notch-like processing and regulated release from primary cilia

Jun-ya Kaimori1, Yasuyuki Nagasawa2, Luis F. Menezes1, Miguel A. Garcia-Gonzalez1, Jie Deng1, Enyu Imai2, Luiz F. Onuchic3, Lisa M. Guay-Woodford4 and Gregory G. Germino1,*

1 Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2 Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan, 3 Division of Nephrology, Department of Medicine, University of Sao Paulo, Sao Paulo, Brazil and 4 Division of Genetic and Translational Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

* To whom correspondence should be addressed at: Department of Medicine, Division of Nephrology, Ross 958, 720 Rutland Avenue, Baltimore, MD 20815, USA. Tel: +1 4106140089; Fax: +1 4106145129; Email: ggermino{at}jhmi.edu

Received August 28, 2006; Revised January 24, 2007; Accepted February 21, 2007

Mutations at a single locus, PKHD1, are responsible for causing human autosomal recessive polycystic kidney disease (ARPKD). Recent studies suggest that the cystic disease might result from defects in planar cell polarity, but how the 4074 amino acid ciliary protein encoded by the longest open reading frame of this transcriptionally complex gene may regulate this process is unknown. Using novel in vitro expression systems, we show that the PKHD1 gene product polyductin/fibrocystin undergoes a complicated pattern of Notch-like proteolytic processing. Cleavage at a probable proprotein convertase site produces a large extracellular domain that is tethered to the C-terminal stalk by disulfide bridges. This fragment is then shed from the primary cilium by activation of a member of the ADAM metalloproteinase disintegrins family, resulting in concomitant release of an intra-cellular C-terminal fragment via a {gamma}-secretase-dependent process. The ectodomain of endogenous PD1 is similarly shed from the primary cilium upon activation of sheddases. This is the first known example of this process involving a protein of the primary cilium and suggests a novel mechanism whereby proteins that localize to this structure may function as bi-directional signaling molecules. Regulated release from the primary cilium into the lumen may be a mechanism to distribute signal to down-stream targets using flow.


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