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

Karsten Boldt; Jeroen Van Reeuwijk; Qianhao Lu; Konstantinos Koutroumpas; Thanh Minh T Nguyen; Yves Texier; Sylvia E C Van Beersum; Nicola Horn; Jason R. Willer; Dorus A. Mans; Gerard Dougherty; Ideke J C Lamers; Karlien L M Coene; Heleen H. Arts; Matthew J. Betts; Tina Beyer; Emine Bolat; Christian Johannes Gloeckner; Khatera Haidari; Lisette Hetterschijt; Daniela Iaconis; Dagan Jenkins; Franziska Klose; Barbara Knapp; Brooke Latour; Stef J F Letteboer; Carlo L. Marcelis; Dragana Mitic; Manuela Morleo; Machteld M. Oud; Moniek Riemersma; Susan Rix; Paulien A. Terhal; Grischa Toedt; Teunis J P Van Dam; Erik De Vrieze; Yasmin Wissinger; Ka Man Wu; Saeed Al-Turki; Carl Anderson; Dinu Antony; Inês Barroso; Jamie Bentham; Shoumo Bhattacharya; Keren Carss; Krishna Chatterjee; Sebahattin Cirak; Catherine Cosgrove; Petr Danecek; Richard Durbin; David Fitzpatrick; Jamie Floyd; A. Reghan Foley; Chris Franklin; Marta Futema; Steve E. Humphries; Matt Hurles; Chris Joyce; Shane McCarthy; Hannah M. Mitchison; Dawn Muddyman; Francesco Muntoni; Stephen O'Rahilly; Alexandros Onoufriadis; Felicity Payne; Vincent Plagnol; Lucy Raymond; David B. Savage; Peter Scambler; Miriam Schmidts; Nadia Schoenmakers; Robert Semple; Eva Serra; Jim Stalker; Margriet Van Kogelenberg; Parthiban Vijayarangakannan; Klaudia Walter; Ros Whittall; Kathy Williamson; Gordana Apic; Philip L. Beales; Oliver E. Blacque; Toby J. Gibson; Martijn A. Huynen; Nicholas Katsanis; Hannie Kremer; Heymut Omran; Erwin Van Wijk; Uwe Wolfrum; François Kepes; Erica E. Davis; Brunella Franco; Rachel H. Giles; Marius Ueffing; Robert B. Russell; Ronald Roepman

doi:10.1038/ncomms11491

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

Karsten Boldt, Jeroen Van Reeuwijk, Qianhao Lu, Konstantinos Koutroumpas, Thanh Minh T Nguyen, Yves Texier, Sylvia E C Van Beersum, Nicola Horn, Jason R. Willer, Dorus A. Mans, Gerard Dougherty, Ideke J C Lamers, Karlien L M Coene, Heleen H. Arts, Matthew J. Betts, Tina Beyer, Emine Bolat, Christian Johannes Gloeckner, Khatera Haidari, Lisette HetterschijtDaniela Iaconis, Dagan Jenkins, Franziska Klose, Barbara Knapp, Brooke Latour, Stef J F Letteboer, Carlo L. Marcelis, Dragana Mitic, Manuela Morleo, Machteld M. Oud, Moniek Riemersma, Susan Rix, Paulien A. Terhal, Grischa Toedt, Teunis J P Van Dam, Erik De Vrieze, Yasmin Wissinger, Ka Man Wu, Saeed Al-Turki, Carl Anderson, Dinu Antony, Inês Barroso, Jamie Bentham, Shoumo Bhattacharya, Keren Carss, Krishna Chatterjee, Sebahattin Cirak, Catherine Cosgrove, Petr Danecek, Richard Durbin, David Fitzpatrick, Jamie Floyd, A. Reghan Foley, Chris Franklin, Marta Futema, Steve E. Humphries, Matt Hurles, Chris Joyce, Shane McCarthy, Hannah M. Mitchison, Dawn Muddyman, Francesco Muntoni, Stephen O'Rahilly, Alexandros Onoufriadis, Felicity Payne, Vincent Plagnol, Lucy Raymond, David B. Savage, Peter Scambler, Miriam Schmidts, Nadia Schoenmakers, Robert Semple, Eva Serra, Jim Stalker, Margriet Van Kogelenberg, Parthiban Vijayarangakannan, Klaudia Walter, Ros Whittall, Kathy Williamson, Gordana Apic, Philip L. Beales, Oliver E. Blacque, Toby J. Gibson, Martijn A. Huynen, Nicholas Katsanis, Hannie Kremer, Heymut Omran, Erwin Van Wijk, Uwe Wolfrum, François Kepes, Erica E. Davis, Brunella Franco, Rachel H. Giles, Marius Ueffing^*, Robert B. Russell, Ronald Roepman

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Article number	11491
Journal	Nature Communications [E]
Volume	7
DOIs	https://doi.org/10.1038/ncomms11491
Publication status	Published - 13 May 2016

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10.1038/ncomms11491

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Boldt, K., Van Reeuwijk, J., Lu, Q., Koutroumpas, K., Nguyen, T. M. T., Texier, Y., Van Beersum, S. E. C., Horn, N., Willer, J. R., Mans, D. A., Dougherty, G., Lamers, I. J. C., Coene, K. L. M., Arts, H. H., Betts, M. J., Beyer, T., Bolat, E., Gloeckner, C. J., Haidari, K., ... Roepman, R. (2016). An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nature Communications [E], 7, Article 11491. https://doi.org/10.1038/ncomms11491

@article{e7de68b8d1434f8999e308fef052bc52,

title = "An organelle-specific protein landscape identifies novel diseases and molecular mechanisms",

abstract = "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.",

author = "Karsten Boldt and {Van Reeuwijk}, Jeroen and Qianhao Lu and Konstantinos Koutroumpas and Nguyen, {Thanh Minh T} and Yves Texier and {Van Beersum}, {Sylvia E C} and Nicola Horn and Willer, {Jason R.} and Mans, {Dorus A.} and Gerard Dougherty and Lamers, {Ideke J C} and Coene, {Karlien L M} and Arts, {Heleen H.} and Betts, {Matthew J.} and Tina Beyer and Emine Bolat and Gloeckner, {Christian Johannes} and Khatera Haidari and Lisette Hetterschijt and Daniela Iaconis and Dagan Jenkins and Franziska Klose and Barbara Knapp and Brooke Latour and Letteboer, {Stef J F} and Marcelis, {Carlo L.} and Dragana Mitic and Manuela Morleo and Oud, {Machteld M.} and Moniek Riemersma and Susan Rix and Terhal, {Paulien A.} and Grischa Toedt and {Van Dam}, {Teunis J P} and {De Vrieze}, Erik and Yasmin Wissinger and Wu, {Ka Man} and Saeed Al-Turki and Carl Anderson and Dinu Antony and In{\^e}s Barroso and Jamie Bentham and Shoumo Bhattacharya and Keren Carss and Krishna Chatterjee and Sebahattin Cirak and Catherine Cosgrove and Petr Danecek and Richard Durbin and David Fitzpatrick and Jamie Floyd and Foley, {A. Reghan} and Chris Franklin and Marta Futema and Humphries, {Steve E.} and Matt Hurles and Chris Joyce and Shane McCarthy and Mitchison, {Hannah M.} and Dawn Muddyman and Francesco Muntoni and Stephen O'Rahilly and Alexandros Onoufriadis and Felicity Payne and Vincent Plagnol and Lucy Raymond and Savage, {David B.} and Peter Scambler and Miriam Schmidts and Nadia Schoenmakers and Robert Semple and Eva Serra and Jim Stalker and {Van Kogelenberg}, Margriet and Parthiban Vijayarangakannan and Klaudia Walter and Ros Whittall and Kathy Williamson and Gordana Apic and Beales, {Philip L.} and Blacque, {Oliver E.} and Gibson, {Toby J.} and Huynen, {Martijn A.} and Nicholas Katsanis and Hannie Kremer and Heymut Omran and {Van Wijk}, Erwin and Uwe Wolfrum and Fran{\c c}ois Kepes and Davis, {Erica E.} and Brunella Franco and Giles, {Rachel H.} and Marius Ueffing and Russell, {Robert B.} and Ronald Roepman",

year = "2016",

month = may,

day = "13",

doi = "10.1038/ncomms11491",

language = "English",

volume = "7",

journal = "Nature Communications [E]",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Boldt, K, Van Reeuwijk, J, Lu, Q, Koutroumpas, K, Nguyen, TMT, Texier, Y, Van Beersum, SEC, Horn, N, Willer, JR, Mans, DA, Dougherty, G, Lamers, IJC, Coene, KLM, Arts, HH, Betts, MJ, Beyer, T, Bolat, E, Gloeckner, CJ, Haidari, K, Hetterschijt, L, Iaconis, D, Jenkins, D, Klose, F, Knapp, B, Latour, B, Letteboer, SJF, Marcelis, CL, Mitic, D, Morleo, M, Oud, MM, Riemersma, M, Rix, S, Terhal, PA, Toedt, G, Van Dam, TJP, De Vrieze, E, Wissinger, Y, Wu, KM, Al-Turki, S, Anderson, C, Antony, D, Barroso, I, Bentham, J, Bhattacharya, S, Carss, K, Chatterjee, K, Cirak, S, Cosgrove, C, Danecek, P, Durbin, R, Fitzpatrick, D, Floyd, J, Foley, AR, Franklin, C, Futema, M, Humphries, SE, Hurles, M, Joyce, C, McCarthy, S, Mitchison, HM, Muddyman, D, Muntoni, F, O'Rahilly, S, Onoufriadis, A, Payne, F, Plagnol, V, Raymond, L, Savage, DB, Scambler, P, Schmidts, M, Schoenmakers, N, Semple, R, Serra, E, Stalker, J, Van Kogelenberg, M, Vijayarangakannan, P, Walter, K, Whittall, R, Williamson, K, Apic, G, Beales, PL, Blacque, OE, Gibson, TJ, Huynen, MA, Katsanis, N, Kremer, H, Omran, H, Van Wijk, E, Wolfrum, U, Kepes, F, Davis, EE, Franco, B, Giles, RH, Ueffing, M, Russell, RB & Roepman, R 2016, 'An organelle-specific protein landscape identifies novel diseases and molecular mechanisms', Nature Communications [E], vol. 7, 11491. https://doi.org/10.1038/ncomms11491

TY - JOUR

T1 - An organelle-specific protein landscape identifies novel diseases and molecular mechanisms

AU - Boldt, Karsten

AU - Van Reeuwijk, Jeroen

AU - Lu, Qianhao

AU - Koutroumpas, Konstantinos

AU - Nguyen, Thanh Minh T

AU - Texier, Yves

AU - Van Beersum, Sylvia E C

AU - Horn, Nicola

AU - Willer, Jason R.

AU - Mans, Dorus A.

AU - Dougherty, Gerard

AU - Lamers, Ideke J C

AU - Coene, Karlien L M

AU - Arts, Heleen H.

AU - Betts, Matthew J.

AU - Beyer, Tina

AU - Bolat, Emine

AU - Gloeckner, Christian Johannes

AU - Haidari, Khatera

AU - Hetterschijt, Lisette

AU - Iaconis, Daniela

AU - Jenkins, Dagan

AU - Klose, Franziska

AU - Knapp, Barbara

AU - Latour, Brooke

AU - Letteboer, Stef J F

AU - Marcelis, Carlo L.

AU - Mitic, Dragana

AU - Morleo, Manuela

AU - Oud, Machteld M.

AU - Riemersma, Moniek

AU - Rix, Susan

AU - Terhal, Paulien A.

AU - Toedt, Grischa

AU - Van Dam, Teunis J P

AU - De Vrieze, Erik

AU - Wissinger, Yasmin

AU - Wu, Ka Man

AU - Al-Turki, Saeed

AU - Anderson, Carl

AU - Antony, Dinu

AU - Barroso, Inês

AU - Bentham, Jamie

AU - Bhattacharya, Shoumo

AU - Carss, Keren

AU - Chatterjee, Krishna

AU - Cirak, Sebahattin

AU - Cosgrove, Catherine

AU - Danecek, Petr

AU - Durbin, Richard

AU - Fitzpatrick, David

AU - Floyd, Jamie

AU - Foley, A. Reghan

AU - Franklin, Chris

AU - Futema, Marta

AU - Humphries, Steve E.

AU - Hurles, Matt

AU - Joyce, Chris

AU - McCarthy, Shane

AU - Mitchison, Hannah M.

AU - Muddyman, Dawn

AU - Muntoni, Francesco

AU - O'Rahilly, Stephen

AU - Onoufriadis, Alexandros

AU - Payne, Felicity

AU - Plagnol, Vincent

AU - Raymond, Lucy

AU - Savage, David B.

AU - Scambler, Peter

AU - Schmidts, Miriam

AU - Schoenmakers, Nadia

AU - Semple, Robert

AU - Serra, Eva

AU - Stalker, Jim

AU - Van Kogelenberg, Margriet

AU - Vijayarangakannan, Parthiban

AU - Walter, Klaudia

AU - Whittall, Ros

AU - Williamson, Kathy

AU - Apic, Gordana

AU - Beales, Philip L.

AU - Blacque, Oliver E.

AU - Gibson, Toby J.

AU - Huynen, Martijn A.

AU - Katsanis, Nicholas

AU - Kremer, Hannie

AU - Omran, Heymut

AU - Van Wijk, Erwin

AU - Wolfrum, Uwe

AU - Kepes, François

AU - Davis, Erica E.

AU - Franco, Brunella

AU - Giles, Rachel H.

AU - Ueffing, Marius

AU - Russell, Robert B.

AU - Roepman, Ronald

PY - 2016/5/13

Y1 - 2016/5/13

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84968718737&partnerID=8YFLogxK

U2 - 10.1038/ncomms11491

DO - 10.1038/ncomms11491

M3 - Article

C2 - 27173435

SN - 2041-1723

VL - 7

JO - Nature Communications [E]

JF - Nature Communications [E]

M1 - 11491

ER -

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

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