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Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis

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 sho...

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Autores principales: Gopalan, Janani, Omar, Mitchell H, Roy, Ankita, Cruz, Nelly M, Falcone, Jerome, Jones, Kiana N, Forbush, Katherine A, Himmelfarb, Jonathan, Freedman, Benjamin S, Scott, John D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291974/
https://www.ncbi.nlm.nih.gov/pubmed/34250905
http://dx.doi.org/10.7554/eLife.67828
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author Gopalan, Janani
Omar, Mitchell H
Roy, Ankita
Cruz, Nelly M
Falcone, Jerome
Jones, Kiana N
Forbush, Katherine A
Himmelfarb, Jonathan
Freedman, Benjamin S
Scott, John D
author_facet Gopalan, Janani
Omar, Mitchell H
Roy, Ankita
Cruz, Nelly M
Falcone, Jerome
Jones, Kiana N
Forbush, Katherine A
Himmelfarb, Jonathan
Freedman, Benjamin S
Scott, John D
author_sort Gopalan, Janani
collection PubMed
description 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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spelling pubmed-82919742021-07-21 Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis Gopalan, Janani Omar, Mitchell H Roy, Ankita Cruz, Nelly M Falcone, Jerome Jones, Kiana N Forbush, Katherine A Himmelfarb, Jonathan Freedman, Benjamin S Scott, John D eLife Biochemistry and Chemical Biology 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. eLife Sciences Publications, Ltd 2021-07-12 /pmc/articles/PMC8291974/ /pubmed/34250905 http://dx.doi.org/10.7554/eLife.67828 Text en © 2021, Gopalan et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Gopalan, Janani
Omar, Mitchell H
Roy, Ankita
Cruz, Nelly M
Falcone, Jerome
Jones, Kiana N
Forbush, Katherine A
Himmelfarb, Jonathan
Freedman, Benjamin S
Scott, John D
Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis
title Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis
title_full Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis
title_fullStr Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis
title_full_unstemmed Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis
title_short Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis
title_sort targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291974/
https://www.ncbi.nlm.nih.gov/pubmed/34250905
http://dx.doi.org/10.7554/eLife.67828
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