期刊
JOURNAL OF CELL BIOLOGY
卷 221, 期 4, 页码 -出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.202010065
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资金
- UCSF Parnassus Flow Cytometry Core [RRID:SCR_018206]
- DRC center grant [NIG P30 DK063720, RF1 AG058476, P01 AG054407, R01 NS124848]
- Michael J Fox Foundation
- Taube Koret Center for Neurodegenerative disease
- Laurel Endowment for Pediatric Craniofacial Research
- Stowers Family Endowed Chair for Dental & Mineralized Tissue Research
- Michael J. Fox Foundation LRRK2 Challenge 2014 [9550]
- Fondazione Banco di Sardegna [2014.0489]
- Fondo di Ateneo per la ricerca 2020
- Fondo di Ateneo per la ricerca 2020 [S10 RR026758]
- National Institutes of Health [R01EY027810, R01CA219815, K08NS090633]
- DoD [W81XWH-18-1-0376]
- American Federation for Aging Research
This study reveals that TRIM1 plays a critical role in regulating the degradation, localization, and kinase activity of LRRK2, which is crucial for familial Parkinson's disease.
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 LRRK2(911-)(919), a nine amino acid segment within a flexible interdomain region (LRRK2(853)(-)(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.
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