Evidence map›Paper›PMID 35266954›Full record

ArticleThe Journal of cell biology2022

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

Adrienne E D Stormo, Farbod Shavarebi, Molly FitzGibbon, Elizabeth M Earley, Hannah Ahrendt, Lotus S Lum, Erik Verschueren, Danielle L Swaney, Gaia Skibinski, Abinaya Ravisankar and 17 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of cell biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.

0numbers the graph read from it
0cells of the map it votes in
10citing papers in PubMed
2.6field-weighted citation impact, top 10% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

10 citing papers in PubMed, 18 citations in OpenAlex.

  1. Review
  2. Article
  3. Review
  4. Review
  5. Review
  6. Article
  7. Article
  8. Review
  9. Article
  10. The Cell Biology of LRRK2 in Parkinson's Disease.Molecular and cellular biology · 2021
    Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

27 authors at 8 institutions in 3 countries.

Adrienne E D StormoDepartments of Pathology, University of California San Francisco, San Francisco, CA.ORCID 0000-0002-4449-2620
Farbod ShavarebiDepartment of Pathology, University of California San Diego, San Diego, CA.ORCID 0000-0003-3627-3097
Molly FitzGibbon *Department of Pathology, University of California San Diego, San Diego, CA.
Elizabeth M Earley *Departments of Pathology, University of California San Francisco, San Francisco, CA.
Hannah Ahrendt *Department of Pathology, University of California San Diego, San Diego, CA.
Lotus S LumDepartments of Pathology, University of California San Francisco, San Francisco, CA.ORCID 0000-0003-4751-0764
Erik VerschuerenDepartments of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA.ORCID 0000-0001-5842-6344
Danielle L SwaneyDepartments of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA.
Gaia SkibinskiTaube/Koret Center for Neurodegenerative Disease Research, J. David Gladstone Institutes, San Francisco, CA.
Abinaya RavisankarTaube/Koret Center for Neurodegenerative Disease Research, J. David Gladstone Institutes, San Francisco, CA.ORCID 0000-0001-8996-126X
Jeffrey van HarenDepartments of Cell and Tissue Biology, University of California San Francisco, San Francisco, CA.ORCID 0000-0002-3160-3547
Emily J DavisDepartments of Pathology, University of California San Francisco, San Francisco, CA.ORCID 0000-0001-9878-1252
Jeffrey R JohnsonDepartments of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA.
John Von DollenDepartments of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA.ORCID 0000-0002-8430-7848
Carson BalenDepartment of Pathology, University of California San Diego, San Diego, CA.
Jacob PorathDepartment of Pathology, University of California San Diego, San Diego, CA.
Claudia CrosioDepartment of Biomedical Sciences, University of Sassari, Sassari, Italy.
Christian MirescuNeuroscience, Merck & Co. Inc., Boston, MA.
Ciro IaccarinoDepartment of Biomedical Sciences, University of Sassari, Sassari, Italy.ORCID 0000-0003-1619-7146
William T DauerDepartments of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX.ORCID 0000-0003-1775-7504
R Jeremy NicholsDepartment of Pathology, Stanford University, Palo Alto, CA.
Torsten WittmannDepartments of Cell and Tissue Biology, University of California San Francisco, San Francisco, CA.ORCID 0000-0001-9134-691X
Timothy C CoxDepartment of Oral and Craniofacial Sciences, School of Medicine, University of Missouri Kansas City, Kansas City, MO.ORCID 0000-0001-8015-5528
Steve FinkbeinerDepartments of Neurology, University of California San Francisco, San Francisco, CA.ORCID 0000-0002-3480-394X
Nevan J KroganDepartments of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA.ORCID 0000-0003-4902-337X
Scott A OakesDepartments of Pathology, University of California San Francisco, San Francisco, CA.
Annie HinikerDepartment of Pathology, University of California San Diego, San Diego, CA.ORCID 0000-0002-0055-6610
University of California, San Francisco · USUniversity of California San Diego · USGladstone Institutes · USUniversity of Sassari · ITMerck & Co., Inc., Rahway, NJ, USA (United States) · USPalo Alto University · USThe University of Texas Southwestern Medical Center · USUniversity of Missouri–Kansas City · US

Funding

Research BaseP30DK063720 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GERMAN, MICHAEL S · 2003 to 2019
$21.8M
The proteasome in aging and neurodegenerative diseaseP01AG054407 · NIA · NORTHWESTERN UNIVERSITY · PI FRYDMAN, JUDITH · 2018 to 2022
$14.0M
Dysfunction of the Autophagy-Lysosomal Pathway as a Common Mechanism of NeurodegenerationRF1AG058476 · NIA · J. DAVID GLADSTONE INSTITUTES · PI FINKBEINER, STEVEN M · 2017 to 2018
$4.1M
Role of the Unfolded Protein Response in Photoreceptor DegenerationR01EY027810 · NEI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GOULD, DOUGLAS, OAKES, SCOTT A. · 2018 to 2022
$3.0M
Targeting the Unfolded Protein Response in PanNETsR01CA219815 · NCI · UNIVERSITY OF CHICAGO · PI OAKES, SCOTT A. · 2018 to 2022
$2.4M
Dissecting the Etiology of The Lewy Body DementiasRF1NS124848 · NINDS · J. DAVID GLADSTONE INSTITUTES · PI BRAS, JOSE, FINKBEINER, STEVEN M · 2022 to 2022
$2.4M
Dissecting the Etiology of The Lewy Body DementiasR01NS124848 · NINDS · J. DAVID GLADSTONE INSTITUTES · PI STEVEN M FINKBEINER · 2025 to 2026
$1.6M
Chemical-Genetic Approaches to Define Lrrk2 Kinase Function in Parkinson DiseaseK08NS090633 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI HINIKER, ANNIE E · 2014 to 2018
$1.1M
Spinning disk confocal / FRAP microscope for quantitative live cell imagingS10RR026758 · NCRR · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI WITTMANN, TORSTEN · 2010 to 2010
$500k
NCI NIH HHS R01 CA219815NCRR NIH HHS S10 RR026758NEI NIH HHS R01 EY027810NIA NIH HHS P01 AG054407NIA NIH HHS RF1 AG058476NIDDK NIH HHS P30 DK063720NIH HHS NIG P30 DK063720NIH HHS R01EY027810NINDS NIH HHS K08 NS090633NINDS NIH HHS R01 NS124848NINDS NIH HHS RF1 NS124848
6 · The paper itself

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 LRRK2911-919, a nine amino acid segment within a flexible interdomain region (LRRK2853-981), which we designate the "regulatory loop" (RL). Phosphorylation of LRRK2 Ser910/Ser935 within LRRK2 RL influences LRRK2's association with cytoplasmic 14-3-3 versus microtubule-bound TRIM1. Association with TRIM1 modulates LRRK2's interaction with Rab29 and prevents upregulation of LRRK2 kinase activity by Rab29 in an E3-ligase-dependent manner. Finally, TRIM1 rescues neurite outgrowth deficits caused by PD-driving mutant LRRK2 G2019S. Our data suggest that TRIM1 is a critical regulator of LRRK2, controlling its degradation, localization, binding partners, kinase activity, and cytotoxicity.

Indexed as

Leucine-Rich Repeat Serine-Threonine Protein Kinase-2Parkinson DiseaseProtein Serine-Threonine KinasesTripartite Motif ProteinsCytoskeletonHumansMicrotubule-Associated ProteinsMicrotubulesMutationPhosphorylationrab GTP-Binding ProteinsTranscription FactorsUbiquitinationUbiquitin-Protein LigasesLeucine-Rich Repeat Serine-Threonine Protein Kinase-2LRRK2 protein, humanMicrotubule-Associated ProteinsMID2 protein, humanProtein Serine-Threonine KinasesRab29 protein, humanrab GTP-Binding ProteinsTranscription FactorsTripartite Motif ProteinsUbiquitin-Protein Ligases

Identifiers

PMID35266954
PMCPMC8919618
OpenAlexW4221005621

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.