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Proximity labeling reveals an extensive steady-state stress granule interactome and insights to neurodegeneration

Sebastian Markmiller, Sahar Soltanieh, Kari Server, Raymond Mak, Wenhao Jin, Enching Luo, Florian Krach, Mark W. Kankel, Anindya Sen, Eric J. Bennett, Eric Lécuyer, Gene W. Yeo
doi: https://doi.org/10.1101/152520
Sebastian Markmiller
1 Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, USA
2 Stem Cell Program, University of California at San Diego, La Jolla, California, USA
3 Institute for Genomic Medicine, University of California at San Diego, La Jolla, California, USA
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Sahar Soltanieh
4 Institut de Recherches Cliniques de Montréal, Montréal, Canada
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Kari Server
1 Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, USA
2 Stem Cell Program, University of California at San Diego, La Jolla, California, USA
3 Institute for Genomic Medicine, University of California at San Diego, La Jolla, California, USA
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Raymond Mak
5 Division of Biological Sciences, University of California at San Diego, La Jolla, California, USA
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Wenhao Jin
6 Département de Biochimie et Médecine Moléculaire, Université de Montréal; Division of Experimental Medicine, McGill University, Montréal, Canada
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Enching Luo
1 Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, USA
2 Stem Cell Program, University of California at San Diego, La Jolla, California, USA
3 Institute for Genomic Medicine, University of California at San Diego, La Jolla, California, USA
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Florian Krach
1 Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, USA
2 Stem Cell Program, University of California at San Diego, La Jolla, California, USA
3 Institute for Genomic Medicine, University of California at San Diego, La Jolla, California, USA
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Mark W. Kankel
7 Neurodegeneration and Repair, Biogen, Cambridge, Massachusetts, USA
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Anindya Sen
7 Neurodegeneration and Repair, Biogen, Cambridge, Massachusetts, USA
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Eric J. Bennett
5 Division of Biological Sciences, University of California at San Diego, La Jolla, California, USA
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Eric Lécuyer
4 Institut de Recherches Cliniques de Montréal, Montréal, Canada
6 Département de Biochimie et Médecine Moléculaire, Université de Montréal; Division of Experimental Medicine, McGill University, Montréal, Canada
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Gene W. Yeo
1 Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, USA
2 Stem Cell Program, University of California at San Diego, La Jolla, California, USA
3 Institute for Genomic Medicine, University of California at San Diego, La Jolla, California, USA
8 Molecular Engineering Laboratory, A*STAR, Singapore
9 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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  • For correspondence: geneyeo@ucsd.edu
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Abstract

Stress granules (SGs) are transient ribonucleoprotein (RNP) aggregates that form in response to proteotoxic stress. Although SGs are distinct from aggregates observed in neurodegenerative disorders, they share protein components. We used APEX-mediated proximity labeling combined with quantitative mass spectrometry and high-throughput imaging to identify >100 previously unknown SG proteins in human cells, about 10% of which localize to SGs in a cell type- or stress type-dependent manner. Supporting a link between SG proteins and neurodegeneration, we demonstrate aberrant SG composition and subcellular distribution in iPSC-derived motor neurons from ALS patients, and identify several known and previously unidentified SG proteins that modify toxicity of mutant FUS and TDP-43 overexpression in Drosophila. We show that even in an unstressed steady-state, SG proteins form a densely-connected protein interaction network (PIN) and propose a model in which existing RNPs coalesce rapidly into microscopically visible granules that can act as gateways to pathological protein aggregation.

Highlights

  • APEX proximity labeling of dynamic RNP granules identifies over 100 novel SG proteins

  • SG proteins form a densely-connected protein interaction network in unstressed cells

  • Systematic immunofluorescence analysis reveals stress- and cell type-specific SG composition

  • ALS motor neurons contain SGs with distinct content and subcellular distribution

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 20, 2017.
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Proximity labeling reveals an extensive steady-state stress granule interactome and insights to neurodegeneration
Sebastian Markmiller, Sahar Soltanieh, Kari Server, Raymond Mak, Wenhao Jin, Enching Luo, Florian Krach, Mark W. Kankel, Anindya Sen, Eric J. Bennett, Eric Lécuyer, Gene W. Yeo
bioRxiv 152520; doi: https://doi.org/10.1101/152520
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Proximity labeling reveals an extensive steady-state stress granule interactome and insights to neurodegeneration
Sebastian Markmiller, Sahar Soltanieh, Kari Server, Raymond Mak, Wenhao Jin, Enching Luo, Florian Krach, Mark W. Kankel, Anindya Sen, Eric J. Bennett, Eric Lécuyer, Gene W. Yeo
bioRxiv 152520; doi: https://doi.org/10.1101/152520

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