The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity.
The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity.
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DOI：
10.1083/jcb.202010065
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发表时间：
2022-04-04
期刊：
影响因子：
--
通讯作者：
Hiniker A
中科院分区：
文献类型：
--
作者：
Stormo AED;Shavarebi F;FitzGibbon M;Earley EM;Ahrendt H;Lum LS;Verschueren E;Swaney DL;Skibinski G;Ravisankar A;van Haren J;Davis EJ;Johnson JR;Von Dollen J;Balen C;Porath J;Crosio C;Mirescu C;Iaccarino C;Dauer WT;Nichols RJ;Wittmann T;Cox TC;Finkbeiner S;Krogan NJ;Oakes SA;Hiniker A
Stormo等人使用基于定量质谱的方法鉴定微管相关E3泛素连接酶TRIM1是帕金森病驱动激酶LRRK2的新型相互作用伙伴。他们发现TRIM1将LRRK2招募到细胞骨架上，并控制其降解、激酶激活和细胞毒性。富亮氨酸重复激酶2 （LRRK2）错义突变是家族性帕金森病（PD）的最常见原因；然而，调控LRRK2亚细胞定位、功能和转换的途径尚未完全确定。我们进行了基于定量质谱的相互作用组研究，鉴定了48种新的LRRK2相互作用体，包括微管相关的E3泛素连接酶TRIM1 （tripartite motif family 1）。TRIM1通过结合LRRK2911-919将LRRK2招募到微管细胞骨架上进行泛素化和蛋白酶体降解，LRRK2911-919是一个位于柔性结构域间区域（LRRK2853-981）的9个氨基酸片段，我们将其称为“调控环”（RL）。LRRK2 RL内LRRK2 Ser910/Ser935的磷酸化影响LRRK2与细胞质14-3-3和微管结合TRIM1的关联。与TRIM1的关联调节了LRRK2与Rab29的相互作用，并以e3连接酶依赖的方式阻止Rab29上调LRRK2激酶活性。最后，TRIM1可以修复由pd驱动突变体LRRK2 G2019S引起的神经突起生长缺陷。我们的数据表明TRIM1是LRRK2的关键调节因子，控制其降解、定位、结合伙伴、激酶活性和细胞毒性。
Stormo et al. use a quantitative mass spectrometry–based approach to identify the microtubule-associated E3 ubiquitin ligase TRIM1 as a novel interacting partner of the Parkinson’s disease–driving kinase LRRK2. They find that TRIM1 recruits LRRK2 to the cytoskeleton and controls its degradation, kinase activation, and cytotoxicity. 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.
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影响因子：
14.8
作者：
Barmada, Sami J.;Serio, Andrea;Arjun, Arpana;Bilican, Bilada;Daub, Aaron;Ando, D. Michael;Tsvetkov, Andrey;Pleiss, Michael;Li, Xingli;Peisach, Daniel;Shaw, Christopher;Chandran, Siddharthan;Finkbeiner, Steven
通讯作者：
Finkbeiner, Steven
DOI：
10.1073/pnas.1318306111
发表时间：
2014-02-18
影响因子：
11.1
作者：
Beilina, Alexandria;Rudenko, Iakov N.;Cookson, Mark R.
通讯作者：
Cookson, Mark R.
影响因子：
5.4
作者：
Klein, Christine;Westenberger, Ana
通讯作者：
Westenberger, Ana
影响因子：
4.8
作者：
Greggio, Elisa;Zambrano, Ibardo;Cookson, Mark R.
通讯作者：
Cookson, Mark R.
影响因子：
3.5
作者：
Kett, Lauren R.;Boassa, Daniela;Dauer, William T.
通讯作者：
Dauer, William T.