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A cAMP signalosome in primary cilia drives gene expression and kidney cyst formation

The primary cilium constitutes an organelle that orchestrates signal transduction independently from the cell body. Dysregulation of this intricate molecular architecture leads to severe human diseases, commonly referred to as ciliopathies. However, the molecular underpinnings how ciliary signaling...

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Autores principales: Hansen, Jan N, Kaiser, Fabian, Leyendecker, Philipp, Stüven, Birthe, Krause, Jens‐Henning, Derakhshandeh, Fatemeh, Irfan, Jaazba, Sroka, Tommy J, Preval, Kenley M, Desai, Paurav B, Kraut, Michael, Theis, Heidi, Drews, Anna‐Dorothee, De‐Domenico, Elena, Händler, Kristian, Pazour, Gregory J, Henderson, David J P, Mick, David U, Wachten, Dagmar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9346484/
https://www.ncbi.nlm.nih.gov/pubmed/35695071
http://dx.doi.org/10.15252/embr.202154315
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author Hansen, Jan N
Kaiser, Fabian
Leyendecker, Philipp
Stüven, Birthe
Krause, Jens‐Henning
Derakhshandeh, Fatemeh
Irfan, Jaazba
Sroka, Tommy J
Preval, Kenley M
Desai, Paurav B
Kraut, Michael
Theis, Heidi
Drews, Anna‐Dorothee
De‐Domenico, Elena
Händler, Kristian
Pazour, Gregory J
Henderson, David J P
Mick, David U
Wachten, Dagmar
author_facet Hansen, Jan N
Kaiser, Fabian
Leyendecker, Philipp
Stüven, Birthe
Krause, Jens‐Henning
Derakhshandeh, Fatemeh
Irfan, Jaazba
Sroka, Tommy J
Preval, Kenley M
Desai, Paurav B
Kraut, Michael
Theis, Heidi
Drews, Anna‐Dorothee
De‐Domenico, Elena
Händler, Kristian
Pazour, Gregory J
Henderson, David J P
Mick, David U
Wachten, Dagmar
author_sort Hansen, Jan N
collection PubMed
description The primary cilium constitutes an organelle that orchestrates signal transduction independently from the cell body. Dysregulation of this intricate molecular architecture leads to severe human diseases, commonly referred to as ciliopathies. However, the molecular underpinnings how ciliary signaling orchestrates a specific cellular output remain elusive. By combining spatially resolved optogenetics with RNA sequencing and imaging, we reveal a novel cAMP signalosome that is functionally distinct from the cytoplasm. We identify the genes and pathways targeted by the ciliary cAMP signalosome and shed light on the underlying mechanisms and downstream signaling. We reveal that chronic stimulation of the ciliary cAMP signalosome transforms kidney epithelia from tubules into cysts. Counteracting this chronic cAMP elevation in the cilium by small molecules targeting activation of phosphodiesterase‐4 long isoforms inhibits cyst growth. Thereby, we identify a novel concept of how the primary cilium controls cellular functions and maintains tissue integrity in a specific and spatially distinct manner and reveal novel molecular components that might be involved in the development of one of the most common genetic diseases, polycystic kidney disease.
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spelling pubmed-93464842022-08-09 A cAMP signalosome in primary cilia drives gene expression and kidney cyst formation Hansen, Jan N Kaiser, Fabian Leyendecker, Philipp Stüven, Birthe Krause, Jens‐Henning Derakhshandeh, Fatemeh Irfan, Jaazba Sroka, Tommy J Preval, Kenley M Desai, Paurav B Kraut, Michael Theis, Heidi Drews, Anna‐Dorothee De‐Domenico, Elena Händler, Kristian Pazour, Gregory J Henderson, David J P Mick, David U Wachten, Dagmar EMBO Rep Articles The primary cilium constitutes an organelle that orchestrates signal transduction independently from the cell body. Dysregulation of this intricate molecular architecture leads to severe human diseases, commonly referred to as ciliopathies. However, the molecular underpinnings how ciliary signaling orchestrates a specific cellular output remain elusive. By combining spatially resolved optogenetics with RNA sequencing and imaging, we reveal a novel cAMP signalosome that is functionally distinct from the cytoplasm. We identify the genes and pathways targeted by the ciliary cAMP signalosome and shed light on the underlying mechanisms and downstream signaling. We reveal that chronic stimulation of the ciliary cAMP signalosome transforms kidney epithelia from tubules into cysts. Counteracting this chronic cAMP elevation in the cilium by small molecules targeting activation of phosphodiesterase‐4 long isoforms inhibits cyst growth. Thereby, we identify a novel concept of how the primary cilium controls cellular functions and maintains tissue integrity in a specific and spatially distinct manner and reveal novel molecular components that might be involved in the development of one of the most common genetic diseases, polycystic kidney disease. John Wiley and Sons Inc. 2022-06-13 /pmc/articles/PMC9346484/ /pubmed/35695071 http://dx.doi.org/10.15252/embr.202154315 Text en © 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Hansen, Jan N
Kaiser, Fabian
Leyendecker, Philipp
Stüven, Birthe
Krause, Jens‐Henning
Derakhshandeh, Fatemeh
Irfan, Jaazba
Sroka, Tommy J
Preval, Kenley M
Desai, Paurav B
Kraut, Michael
Theis, Heidi
Drews, Anna‐Dorothee
De‐Domenico, Elena
Händler, Kristian
Pazour, Gregory J
Henderson, David J P
Mick, David U
Wachten, Dagmar
A cAMP signalosome in primary cilia drives gene expression and kidney cyst formation
title A cAMP signalosome in primary cilia drives gene expression and kidney cyst formation
title_full A cAMP signalosome in primary cilia drives gene expression and kidney cyst formation
title_fullStr A cAMP signalosome in primary cilia drives gene expression and kidney cyst formation
title_full_unstemmed A cAMP signalosome in primary cilia drives gene expression and kidney cyst formation
title_short A cAMP signalosome in primary cilia drives gene expression and kidney cyst formation
title_sort camp signalosome in primary cilia drives gene expression and kidney cyst formation
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9346484/
https://www.ncbi.nlm.nih.gov/pubmed/35695071
http://dx.doi.org/10.15252/embr.202154315
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