RT Journal Article
SR Electronic
T1 The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.21.336578
DO 10.1101/2020.10.21.336578
A1 Stormo, Adrienne E. D.
A1 FitzGibbon, Molly
A1 Shavarebi, Farbod
A1 Earley, Elizabeth M.
A1 Lum, Lotus S.
A1 Verschueren, Erik
A1 Swaney, Danielle L.
A1 Skibinski, Gaia
A1 Ravisankar, Abinaya
A1 van Haren, Jeffrey
A1 Davis, Emily J.
A1 Johnson, Jeffrey R.
A1 Von Dollen, John
A1 Mirescu, Christian
A1 Iaccarino, Ciro
A1 Dauer, William T.
A1 Nichols, R. Jeremy
A1 Wittmann, Torsten
A1 Cox, Timothy C.
A1 Finkbeiner, Steve
A1 Krogan, Nevan J.
A1 Oakes, Scott A.
A1 Hiniker, Annie
YR 2020
UL http://biorxiv.org/content/early/2020/10/21/2020.10.21.336578.abstract
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.