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

Abstract

AbstractCellular 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.

Autoren

Karsten Boldt
Jeroen van Reeuwijk
Qianhao Lu
Konstantinos Koutroumpas
Thanh-Minh T Nguyen
Yves Texier
Sylvia EC van Beersum
Nicola Horn
Jason R Willer
Dorus A Mans
Gerard Dougherty
Ideke JC Lamers
Karlien LM 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 JF Letteboer
Carlo L Marcelis
Dragana Mitic
Manuela Morleo
Machteld M Oud
Moniek Riemersma
Susan Rix
Paulien A Terhal
Grischa Toedt
Teunis JP van Dam
Erik de Vrieze
Yasmin Wissinger
Ka Man Wu
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
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

DOI

10.1038/ncomms11491

eISSN

2041-1723

Ausgabe der Veröffentlichung

1

Zeitschrift

Nature Communications

Sprache

en

Artikelnummer

11491

Online publication date

2016

Status

Published online

Herausgeber

Springer Science and Business Media LLC

Herausgeber URL

http://dx.doi.org/10.1038/ncomms11491

Datum der Datenerfassung

2023

Titel

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

Ausgabe der Zeitschrift

7

Datenquelle: Crossref

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.

Addresses

Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen, 72074 Tuebingen, Germany.

Autoren

Karsten Boldt
Jeroen van Reeuwijk
Qianhao Lu
Konstantinos Koutroumpas
Thanh-Minh T Nguyen
Yves Texier
Sylvia EC van Beersum
Nicola Horn
Jason R Willer
Dorus A Mans
Gerard Dougherty
Ideke JC Lamers
Karlien LM 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 JF Letteboer
Carlo L Marcelis
Dragana Mitic
Manuela Morleo
Machteld M Oud
Moniek Riemersma
Susan Rix
Paulien A Terhal
Grischa Toedt
Teunis JP van Dam
Erik de Vrieze
Yasmin Wissinger
Ka Man Wu
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
Robert B Russell
Ronald Roepman
UK10K Rare Diseases Group

DOI

10.1038/ncomms11491

eISSN

2041-1723

Externe Identifier

PubMed Identifier: 27173435
PubMed Central ID: PMC4869170

Funding acknowledgements

NEI NIH HHS: R01 EY021872
Dutch Research Council (NWO): 016.136.091
National Institute for Health Research (NIHR): NF-SI-0507-10380
National Institute for Health Research (NIHR): NF-SI-0513-10109
NIDDK NIH HHS: R01 DK072301
British Heart Foundation: RG/10/17/28553
NIGMS NIH HHS: R01 GM121317
NIDDK NIH HHS: R01 DK075972
Telethon: TGM11CB3
NICHD NIH HHS: R01 HD042601

Open access

true

ISSN

2041-1723

Zeitschrift

Nature communications

Schlüsselwörter

UK10K Rare Diseases Group
Spine
Cilia
Fibroblasts
Humans
Dwarfism
Muscle Hypotonia
Proteins
Chromatography, Affinity
DNA Mutational Analysis
Protein Interaction Mapping
Proteomics
Biological Transport
Systems Analysis
Mass Spectrometry
HEK293 Cells
Molecular Targeted Therapy
Protein Interaction Maps
Datasets as Topic
Ciliopathies

Sprache

eng

Medium

Electronic

Online publication date

2016

Open access status

Open Access

Paginierung

11491

Datum der Veröffentlichung

2016

Status

Published

Publisher licence

CC BY

Datum der Datenerfassung

2016

Titel

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

Sub types

Research Support, Non-U.S. Gov't
research-article
Journal Article
Research Support, N.I.H., Extramural

Ausgabe der Zeitschrift

7

Files

https://www.nature.com/articles/ncomms11491.pdf https://europepmc.org/articles/PMC4869170?pdf=render

Datenquelle: Europe PubMed Central

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.

Date of acceptance

2016

Autoren

Karsten Boldt
Jeroen van Reeuwijk
Qianhao Lu
Konstantinos Koutroumpas
Thanh-Minh T Nguyen
Yves Texier
Sylvia EC van Beersum
Nicola Horn
Jason R Willer
Dorus A Mans
Gerard Dougherty
Ideke JC Lamers
Karlien LM 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 JF Letteboer
Carlo L Marcelis
Dragana Mitic
Manuela Morleo
Machteld M Oud
Moniek Riemersma
Susan Rix
Paulien A Terhal
Grischa Toedt
Teunis JP van Dam
Erik de Vrieze
Yasmin Wissinger
Ka Man Wu
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
UK10K Rare Diseases Group

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/27173435

DOI

10.1038/ncomms11491

eISSN

2041-1723

Externe Identifier

PubMed Central ID: PMC4869170

Funding acknowledgements

NEI NIH HHS: R01 EY021872
NIGMS NIH HHS: R01 GM121317
NIDDK NIH HHS: R01 DK072301
British Heart Foundation: RG/10/17/28553
NIDDK NIH HHS: R01 DK075972
NICHD NIH HHS: R01 HD042601

Zeitschrift

Nat Commun

Schlüsselwörter

Biological Transport
Chromatography, Affinity
Cilia
Ciliopathies
DNA Mutational Analysis
Datasets as Topic
Dwarfism
Fibroblasts
HEK293 Cells
Humans
Mass Spectrometry
Molecular Targeted Therapy
Muscle Hypotonia
Protein Interaction Mapping
Protein Interaction Maps
Proteins
Proteomics
Spine
Systems Analysis

Sprache

eng

Country

England

Paginierung

11491

PII

ncomms11491

Datum der Veröffentlichung

2016

Status

Published online

Datum, an dem der Datensatz öffentlich gemacht wurde

2018

Titel

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

Sub types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

7

Datenquelle: PubMed

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

Files

Werkzeuge