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, Jeffrey van Haren, Emily J. Davis, Jeffrey R. Johnson, John Von Dollen, Carson Balen, Jacob Porath, Claudia Crosio, Christian Mirescu, Ciro Iaccarino, William T. DauerR. Jeremy Nichols, Torsten Wittmann, Timothy C. Cox, Steve Finkbeiner, Nevan J. Krogan, Scott A. Oakes, Annie Hiniker

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere202010065
JournalJournal of Cell Biology
Volume221
Issue number4
DOIs
StatePublished - Apr 4 2022

ASJC Scopus subject areas

  • Cell Biology

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