PT  - JOURNAL ARTICLE
AU  - Stormo, Adrienne E. D.
AU  - FitzGibbon, Molly
AU  - Shavarebi, Farbod
AU  - Earley, Elizabeth M.
AU  - Lum, Lotus S.
AU  - Verschueren, Erik
AU  - Swaney, Danielle L.
AU  - Skibinski, Gaia
AU  - Ravisankar, Abinaya
AU  - van Haren, Jeffrey
AU  - Davis, Emily J.
AU  - Johnson, Jeffrey R.
AU  - Von Dollen, John
AU  - Mirescu, Christian
AU  - Iaccarino, Ciro
AU  - Dauer, William T.
AU  - Nichols, R. Jeremy
AU  - Wittmann, Torsten
AU  - Cox, Timothy C.
AU  - Finkbeiner, Steve
AU  - Krogan, Nevan J.
AU  - Oakes, Scott A.
AU  - Hiniker, Annie
TI  - The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity
AID  - 10.1101/2020.10.21.336578
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.10.21.336578
4099  - http://biorxiv.org/content/early/2020/10/21/2020.10.21.336578.short
4100  - http://biorxiv.org/content/early/2020/10/21/2020.10.21.336578.full
AB  - 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 StatementThe authors have declared no competing interest.