{"doi":"10.1083/jcb.202010065","title":"The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity","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.","journal":"The Journal of Cell Biology","year":2022,"id":257344,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9634,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":571590,"name":"Farbod Shavarebi","orcid":"0000-0003-3627-3097","position":1,"is_corresponding":false},{"id":572089,"name":"Molly FitzGibbon","orcid":null,"position":2,"is_corresponding":false},{"id":572090,"name":"Elizabeth M. 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Jeremy Nichols","orcid":"0000-0002-5228-7571","position":20,"is_corresponding":false},{"id":58366,"name":"Torsten Wittmann","orcid":"0000-0001-9134-691X","position":21,"is_corresponding":false},{"id":438342,"name":"Timothy C. Cox","orcid":"0000-0001-8015-5528","position":22,"is_corresponding":false},{"id":411615,"name":"Steven Finkbeiner","orcid":"0000-0002-3480-394X","position":23,"is_corresponding":false},{"id":1363,"name":"Nevan J. Krogan","orcid":"0000-0003-4902-337X","position":24,"is_corresponding":false},{"id":228910,"name":"Scott A. Oakes","orcid":"0000-0003-2099-2249","position":25,"is_corresponding":false},{"id":467766,"name":"Annie Hiniker","orcid":"0000-0002-0055-6610","position":26,"is_corresponding":false},{"id":571589,"name":"Adrienne E.D. 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