: 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.

The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity / Stormo, Adrienne E D; Shavarebi, Farbod; FitzGibbon, Molly; Earley, Elizabeth M; Ahrendt, Hannah; Lum, Lotus S; Verschueren, Erik; Swaney, Danielle L; Skibinski, Gaia; Ravisankar, Abinaya; van Haren, Jeffrey; Davis, Emily J; Johnson, Jeffrey R; Von Dollen, John; Balen, Carson; Porath, Jacob; Crosio, Claudia; Mirescu, Christian; Iaccarino, Ciro; Dauer, William T; Nichols, R Jeremy; Wittmann, Torsten; Cox, Timothy C; Finkbeiner, Steve; Krogan, Nevan J; Oakes, Scott A; Hiniker, Annie. - In: THE JOURNAL OF CELL BIOLOGY. - ISSN 0021-9525. - 221:4(2022). [10.1083/jcb.202010065]

The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity

Crosio, Claudia;Iaccarino, Ciro;
2022

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.
The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity / Stormo, Adrienne E D; Shavarebi, Farbod; FitzGibbon, Molly; Earley, Elizabeth M; Ahrendt, Hannah; Lum, Lotus S; Verschueren, Erik; Swaney, Danielle L; Skibinski, Gaia; Ravisankar, Abinaya; van Haren, Jeffrey; Davis, Emily J; Johnson, Jeffrey R; Von Dollen, John; Balen, Carson; Porath, Jacob; Crosio, Claudia; Mirescu, Christian; Iaccarino, Ciro; Dauer, William T; Nichols, R Jeremy; Wittmann, Torsten; Cox, Timothy C; Finkbeiner, Steve; Krogan, Nevan J; Oakes, Scott A; Hiniker, Annie. - In: THE JOURNAL OF CELL BIOLOGY. - ISSN 0021-9525. - 221:4(2022). [10.1083/jcb.202010065]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11388/256912
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