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An organelle-specific protein landscape identifies novel diseases and molecular mechanisms

Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a...

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Autores principales: Boldt, Karsten, van Reeuwijk, Jeroen, Lu, Qianhao, Koutroumpas, Konstantinos, Nguyen, Thanh-Minh T., Texier, Yves, van Beersum, Sylvia E. C., Horn, Nicola, Willer, Jason R., Mans, Dorus A., Dougherty, Gerard, Lamers, Ideke J. C., Coene, Karlien L. M., Arts, Heleen H., Betts, Matthew J., Beyer, Tina, Bolat, Emine, Gloeckner, Christian Johannes, Haidari, Khatera, Hetterschijt, Lisette, Iaconis, Daniela, Jenkins, Dagan, Klose, Franziska, Knapp, Barbara, Latour, Brooke, Letteboer, Stef J. F., Marcelis, Carlo L., Mitic, Dragana, Morleo, Manuela, Oud, Machteld M., Riemersma, Moniek, Rix, Susan, Terhal, Paulien A., Toedt, Grischa, van Dam, Teunis J. P., de Vrieze, Erik, Wissinger, Yasmin, Wu, Ka Man, Apic, Gordana, Beales, Philip L., Blacque, Oliver E., Gibson, Toby J., Huynen, Martijn A., Katsanis, Nicholas, Kremer, Hannie, Omran, Heymut, van Wijk, Erwin, Wolfrum, Uwe, Kepes, François, Davis, Erica E., Franco, Brunella, Giles, Rachel H., Ueffing, Marius, Russell, Robert B., Roepman, Ronald
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869170/
https://www.ncbi.nlm.nih.gov/pubmed/27173435
http://dx.doi.org/10.1038/ncomms11491
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author Boldt, Karsten
van Reeuwijk, Jeroen
Lu, Qianhao
Koutroumpas, Konstantinos
Nguyen, Thanh-Minh T.
Texier, Yves
van Beersum, Sylvia E. C.
Horn, Nicola
Willer, Jason R.
Mans, Dorus A.
Dougherty, Gerard
Lamers, Ideke J. C.
Coene, Karlien L. M.
Arts, Heleen H.
Betts, Matthew J.
Beyer, Tina
Bolat, Emine
Gloeckner, Christian Johannes
Haidari, Khatera
Hetterschijt, Lisette
Iaconis, Daniela
Jenkins, Dagan
Klose, Franziska
Knapp, Barbara
Latour, Brooke
Letteboer, Stef J. F.
Marcelis, Carlo L.
Mitic, Dragana
Morleo, Manuela
Oud, Machteld M.
Riemersma, Moniek
Rix, Susan
Terhal, Paulien A.
Toedt, Grischa
van Dam, Teunis J. P.
de Vrieze, Erik
Wissinger, Yasmin
Wu, Ka Man
Apic, Gordana
Beales, Philip L.
Blacque, Oliver E.
Gibson, Toby J.
Huynen, Martijn A.
Katsanis, Nicholas
Kremer, Hannie
Omran, Heymut
van Wijk, Erwin
Wolfrum, Uwe
Kepes, François
Davis, Erica E.
Franco, Brunella
Giles, Rachel H.
Ueffing, Marius
Russell, Robert B.
Roepman, Ronald
author_facet Boldt, Karsten
van Reeuwijk, Jeroen
Lu, Qianhao
Koutroumpas, Konstantinos
Nguyen, Thanh-Minh T.
Texier, Yves
van Beersum, Sylvia E. C.
Horn, Nicola
Willer, Jason R.
Mans, Dorus A.
Dougherty, Gerard
Lamers, Ideke J. C.
Coene, Karlien L. M.
Arts, Heleen H.
Betts, Matthew J.
Beyer, Tina
Bolat, Emine
Gloeckner, Christian Johannes
Haidari, Khatera
Hetterschijt, Lisette
Iaconis, Daniela
Jenkins, Dagan
Klose, Franziska
Knapp, Barbara
Latour, Brooke
Letteboer, Stef J. F.
Marcelis, Carlo L.
Mitic, Dragana
Morleo, Manuela
Oud, Machteld M.
Riemersma, Moniek
Rix, Susan
Terhal, Paulien A.
Toedt, Grischa
van Dam, Teunis J. P.
de Vrieze, Erik
Wissinger, Yasmin
Wu, Ka Man
Apic, Gordana
Beales, Philip L.
Blacque, Oliver E.
Gibson, Toby J.
Huynen, Martijn A.
Katsanis, Nicholas
Kremer, Hannie
Omran, Heymut
van Wijk, Erwin
Wolfrum, Uwe
Kepes, François
Davis, Erica E.
Franco, Brunella
Giles, Rachel H.
Ueffing, Marius
Russell, Robert B.
Roepman, Ronald
author_sort Boldt, Karsten
collection PubMed
description Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine.
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spelling pubmed-48691702016-05-26 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms Boldt, Karsten van Reeuwijk, Jeroen Lu, Qianhao Koutroumpas, Konstantinos Nguyen, Thanh-Minh T. Texier, Yves van Beersum, Sylvia E. C. Horn, Nicola Willer, Jason R. Mans, Dorus A. Dougherty, Gerard Lamers, Ideke J. C. Coene, Karlien L. M. Arts, Heleen H. Betts, Matthew J. Beyer, Tina Bolat, Emine Gloeckner, Christian Johannes Haidari, Khatera Hetterschijt, Lisette Iaconis, Daniela Jenkins, Dagan Klose, Franziska Knapp, Barbara Latour, Brooke Letteboer, Stef J. F. Marcelis, Carlo L. Mitic, Dragana Morleo, Manuela Oud, Machteld M. Riemersma, Moniek Rix, Susan Terhal, Paulien A. Toedt, Grischa van Dam, Teunis J. P. de Vrieze, Erik Wissinger, Yasmin Wu, Ka Man Apic, Gordana Beales, Philip L. Blacque, Oliver E. Gibson, Toby J. Huynen, Martijn A. Katsanis, Nicholas Kremer, Hannie Omran, Heymut van Wijk, Erwin Wolfrum, Uwe Kepes, François Davis, Erica E. Franco, Brunella Giles, Rachel H. Ueffing, Marius Russell, Robert B. Roepman, Ronald Nat Commun Article Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine. Nature Publishing Group 2016-05-13 /pmc/articles/PMC4869170/ /pubmed/27173435 http://dx.doi.org/10.1038/ncomms11491 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Boldt, Karsten
van Reeuwijk, Jeroen
Lu, Qianhao
Koutroumpas, Konstantinos
Nguyen, Thanh-Minh T.
Texier, Yves
van Beersum, Sylvia E. C.
Horn, Nicola
Willer, Jason R.
Mans, Dorus A.
Dougherty, Gerard
Lamers, Ideke J. C.
Coene, Karlien L. M.
Arts, Heleen H.
Betts, Matthew J.
Beyer, Tina
Bolat, Emine
Gloeckner, Christian Johannes
Haidari, Khatera
Hetterschijt, Lisette
Iaconis, Daniela
Jenkins, Dagan
Klose, Franziska
Knapp, Barbara
Latour, Brooke
Letteboer, Stef J. F.
Marcelis, Carlo L.
Mitic, Dragana
Morleo, Manuela
Oud, Machteld M.
Riemersma, Moniek
Rix, Susan
Terhal, Paulien A.
Toedt, Grischa
van Dam, Teunis J. P.
de Vrieze, Erik
Wissinger, Yasmin
Wu, Ka Man
Apic, Gordana
Beales, Philip L.
Blacque, Oliver E.
Gibson, Toby J.
Huynen, Martijn A.
Katsanis, Nicholas
Kremer, Hannie
Omran, Heymut
van Wijk, Erwin
Wolfrum, Uwe
Kepes, François
Davis, Erica E.
Franco, Brunella
Giles, Rachel H.
Ueffing, Marius
Russell, Robert B.
Roepman, Ronald
An organelle-specific protein landscape identifies novel diseases and molecular mechanisms
title An organelle-specific protein landscape identifies novel diseases and molecular mechanisms
title_full An organelle-specific protein landscape identifies novel diseases and molecular mechanisms
title_fullStr An organelle-specific protein landscape identifies novel diseases and molecular mechanisms
title_full_unstemmed An organelle-specific protein landscape identifies novel diseases and molecular mechanisms
title_short An organelle-specific protein landscape identifies novel diseases and molecular mechanisms
title_sort organelle-specific protein landscape identifies novel diseases and molecular mechanisms
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869170/
https://www.ncbi.nlm.nih.gov/pubmed/27173435
http://dx.doi.org/10.1038/ncomms11491
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