Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity

View ORCID ProfileAdrienne E. D. Stormo, Molly FitzGibbon, Farbod Shavarebi, Elizabeth M. Earley, Lotus S. Lum, Erik Verschueren, Danielle L. Swaney, Gaia Skibinski, Abinaya Ravisankar, Jeffrey van Haren, View ORCID ProfileEmily J. Davis, Jeffrey R. Johnson, John Von Dollen, Christian Mirescu, Ciro Iaccarino, William T. Dauer, R. Jeremy Nichols, Torsten Wittmann, Timothy C. Cox, Steve Finkbeiner, Nevan J. Krogan, Scott A. Oakes, View ORCID ProfileAnnie Hiniker
doi: https://doi.org/10.1101/2020.10.21.336578
Adrienne E. D. Stormo
1Departments of Pathology, University of California San Francisco, San Francisco, CA, 94143, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Adrienne E. D. Stormo
Molly FitzGibbon
18Department of Pathology, University of California, San Diego, CA, 92093, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Farbod Shavarebi
18Department of Pathology, University of California, San Diego, CA, 92093, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elizabeth M. Earley
1Departments of Pathology, University of California San Francisco, San Francisco, CA, 94143, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lotus S. Lum
1Departments of Pathology, University of California San Francisco, San Francisco, CA, 94143, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Erik Verschueren
2Departments of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, 94143, U.S.A
6Departments of Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, 94143, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Danielle L. Swaney
2Departments of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, 94143, U.S.A
6Departments of Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, 94143, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gaia Skibinski
7Taube/Koret Center for Neurodegenerative Disease Research, J. David Gladstone Institutes, San Francisco, CA, 94158, U.S.A
8Center for Systems and Therapeutics, J. David Gladstone Institutes, San Francisco, CA, 94158, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Abinaya Ravisankar
7Taube/Koret Center for Neurodegenerative Disease Research, J. David Gladstone Institutes, San Francisco, CA, 94158, U.S.A
8Center for Systems and Therapeutics, J. David Gladstone Institutes, San Francisco, CA, 94158, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jeffrey van Haren
3Departments of Cell and Tissue Biology, University of California San Francisco, San Francisco, CA, 94143, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Emily J. Davis
1Departments of Pathology, University of California San Francisco, San Francisco, CA, 94143, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Emily J. Davis
Jeffrey R. Johnson
2Departments of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, 94143, U.S.A
6Departments of Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, 94143, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John Von Dollen
2Departments of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, 94143, U.S.A
6Departments of Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, 94143, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christian Mirescu
9Neuroscience, Merck & Co. Inc., Boston, MA USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ciro Iaccarino
10Department of Biomedical Sciences, University of Sassari, Sassari, Italy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
William T. Dauer
11Departments of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, 75380, U.S.A
12Departments of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, 75380, U.S.A
13Departments of Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75380, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
R. Jeremy Nichols
14Department of Pathology Stanford University, Palo Alto, CA, 94304, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Torsten Wittmann
3Departments of Cell and Tissue Biology, University of California San Francisco, San Francisco, CA, 94143, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Timothy C. Cox
15Department of Oral and Craniofacial Sciences, School of Medicine, University of Missouri Kansas City, Kansas City, MO, 64108, U.S.A
16School of Dentistry, and Department of Pediatrics, School of Medicine, University of Missouri Kansas City, Kansas City, MO, 64108, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steve Finkbeiner
4Departments of Neurology, University of California San Francisco, San Francisco, CA, 94143, U.S.A
5Departments of Physiology, University of California San Francisco, San Francisco, CA, 94143, U.S.A
7Taube/Koret Center for Neurodegenerative Disease Research, J. David Gladstone Institutes, San Francisco, CA, 94158, U.S.A
8Center for Systems and Therapeutics, J. David Gladstone Institutes, San Francisco, CA, 94158, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nevan J. Krogan
2Departments of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, 94143, U.S.A
6Departments of Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA, 94143, U.S.A
8Center for Systems and Therapeutics, J. David Gladstone Institutes, San Francisco, CA, 94158, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Scott A. Oakes
1Departments of Pathology, University of California San Francisco, San Francisco, CA, 94143, U.S.A
17Department of Pathology, University of Chicago, Chicago, IL, 60637, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: soakes@bsd.uchicago.edu ahiniker@ucsd.edu
Annie Hiniker
1Departments of Pathology, University of California San Francisco, San Francisco, CA, 94143, U.S.A
18Department of Pathology, University of California, San Diego, CA, 92093, U.S.A
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Annie Hiniker
  • For correspondence: soakes@bsd.uchicago.edu ahiniker@ucsd.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s Disease (PD); however, pathways regulating LRRK2 subcellular localization, function, and turnover are not fully defined. We performed quantitative mass spectrometry-based interactome studies to identify 48 novel LRRK2 interactors, including the microtubule-associated E3 ubiquitin ligase TRIM1 (Tripartite Motif Family 1). TRIM1 recruits LRRK2 to the microtubule cytoskeleton for ubiquitination and proteasomal degradation by binding LRRK2822-982, a flexible interdomain region we designate the “Regulatory Loop” (RL). Phosphorylation of LRRK2 Ser910/935 within LRRK2 RL serves as a molecular switch controlling LRRK2’s association with cytoplasmic 14-3-3 versus microtubule-bound TRIM1. Association with TRIM1 prevents upregulation of LRRK2 kinase activity by Rab29 and also rescues neurite outgrowth deficits caused by PD-driving mutant LRRK2 G2019S. Our data suggest that TRIM1 is a critical regulator of LRRK2, modulating its cytoskeletal recruitment, turnover, kinase activity, and cytotoxicity.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted October 21, 2020.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity
Adrienne E. D. Stormo, Molly FitzGibbon, Farbod Shavarebi, Elizabeth M. Earley, Lotus S. Lum, Erik Verschueren, Danielle L. Swaney, Gaia Skibinski, Abinaya Ravisankar, Jeffrey van Haren, Emily J. Davis, Jeffrey R. Johnson, John Von Dollen, Christian Mirescu, Ciro Iaccarino, William T. Dauer, R. Jeremy Nichols, Torsten Wittmann, Timothy C. Cox, Steve Finkbeiner, Nevan J. Krogan, Scott A. Oakes, Annie Hiniker
bioRxiv 2020.10.21.336578; doi: https://doi.org/10.1101/2020.10.21.336578
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity
Adrienne E. D. Stormo, Molly FitzGibbon, Farbod Shavarebi, Elizabeth M. Earley, Lotus S. Lum, Erik Verschueren, Danielle L. Swaney, Gaia Skibinski, Abinaya Ravisankar, Jeffrey van Haren, Emily J. Davis, Jeffrey R. Johnson, John Von Dollen, Christian Mirescu, Ciro Iaccarino, William T. Dauer, R. Jeremy Nichols, Torsten Wittmann, Timothy C. Cox, Steve Finkbeiner, Nevan J. Krogan, Scott A. Oakes, Annie Hiniker
bioRxiv 2020.10.21.336578; doi: https://doi.org/10.1101/2020.10.21.336578

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Molecular Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3602)
  • Biochemistry (7569)
  • Bioengineering (5524)
  • Bioinformatics (20792)
  • Biophysics (10328)
  • Cancer Biology (7981)
  • Cell Biology (11638)
  • Clinical Trials (138)
  • Developmental Biology (6603)
  • Ecology (10202)
  • Epidemiology (2065)
  • Evolutionary Biology (13617)
  • Genetics (9541)
  • Genomics (12847)
  • Immunology (7921)
  • Microbiology (19541)
  • Molecular Biology (7657)
  • Neuroscience (42096)
  • Paleontology (308)
  • Pathology (1258)
  • Pharmacology and Toxicology (2202)
  • Physiology (3267)
  • Plant Biology (7041)
  • Scientific Communication and Education (1294)
  • Synthetic Biology (1951)
  • Systems Biology (5426)
  • Zoology (1117)