Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis
- University of Washington, United States
- University of Washington Medical Center, United States
Abstract
Pathophysiological defects in water homeostasis can lead to renal failure. Likewise, common genetic disorders associated with abnormal cytoskeletal dynamics in the kidney collecting ducts and perturbed calcium and cAMP signaling in the ciliary compartment contribute to chronic kidney failure. We show that collecting ducts in mice lacking the A-Kinase anchoring protein AKAP220 exhibit enhanced development of primary cilia. Mechanistic studies reveal that AKAP220-associated protein phosphatase 1 (PP1) mediates this phenotype by promoting changes in the stability of histone deacetylase 6 (HDAC6) with concomitant defects in actin dynamics. This proceeds through a previously unrecognized adaptor function for PP1 as all ciliogenesis and cytoskeletal phenotypes are recapitulated in mIMCD3 knock-in cells expressing a phosphatase-targeting defective AKAP220-ΔPP1 mutant. Pharmacological blocking of local HDAC6 activity alters cilia development and reduces cystogenesis in kidney-on-chip and organoid models. These findings identify the AKAP220-PPI-HDAC6 pathway as a key effector in primary cilia development.
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All data generated or analyzed during this study are included in the manuscript.
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Author details
Katherine A Forbush
Funding
National Institutes of Health (5R01DK105542)
- John D Scott
National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK119192-01)
- John D Scott
National Institutes of Health (T32 GM007270)
- Janani Gopalan
National Institute of Diabetes and Digestive and Kidney Diseases (F32DK121415)
- Mitchell H Omar
Lara Nowak Macklin Research Fund
- Mitchell H Omar
National Institutes of Health (UG3TR002158)
- Jonathan Himmelfarb
National Institutes of Health (R01DK117914)
- Benjamin S Freedman
The funding information is provided above. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Gopalan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis
eLife 10:e67828.
https://doi.org/10.7554/eLife.67828
