LRRK2-mediated phosphorylation of HDAC6 regulates HDAC6-cytoplasmic dynein interaction and aggresome formation
LRRK2-mediated phosphorylation of HDAC6 regulates HDAC6-cytoplasmic dynein interaction and aggresome formation
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LRRK2 介导的 HDAC6 磷酸化调节 HDAC6-细胞质动力蛋白相互作用和聚集体形成
DOI：
10.1101/554881
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Lucas R
中科院分区：
文献类型：
--
作者：
Lucas R
LRRK2基因突变是显性遗传性帕金森病(PD)的最常见原因。部分LRRK2PD表现为路易氏病变，α-突触核蛋白和泛素在细胞内聚集，与特发性PD难以区分。LRRK2是一个具有GTP酶和激酶活性的多结构域蛋白，它被证明影响包括蛋白质动态平衡在内的各种细胞过程，然而LRRK2中的PD突变如何导致泛素化蛋白质聚集体的积累尚不清楚。去除聚集的泛素化蛋白质的一个主要细胞途径是聚集性吞噬：组蛋白去乙酰基酶HDAC6识别泛素化的错误折叠的蛋白质，并将它们招募到分子马达细胞质动力中，在那里它们被困在侵袭体中，在那里它们被捕获在侵袭体中，随后被宏观自噬移除。我们将HDAC6确定为一种新的LRRK2底物，并表明LRRK2调节依赖HD6的侵袭体的形成。LRRK2通过其ROC结构域直接与HDAC6脱乙酰基酶结构域相互作用，并在丝氨酸-22上磷酸化HDAC6。HDAC6的丝氨酸-22磷酸化增强了它与胞浆动力蛋白的相互作用，并刺激泛素化蛋白向侵袭体募集。LRRK2基因敲除或敲除会削弱HDAC6介导的侵袭体形成。PD突变体LRRK2 G2019S与HDAC6的相互作用减弱，不支持与野生型LRRK2相同程度的侵袭体形成。这一点在LRRK2 G2019S患者来源的星形胶质细胞中得到了概括，显示出侵袭性形成缺陷。总之，我们的数据揭示了HDAC6是LRRK2的靶标，并提示HDAC6介导的侵袭体形成和吞噬作用的放松可能在PD的病理中起作用。
Mutations in LRRK2 are the most common cause of dominantly inherited Parkinson’s disease (PD). A proportion of LRRK2 PD exhibits Lewy pathology with accumulations of α-synuclein and ubiquitin in intracellular aggregates that are indistinguishable from idiopathic PD. LRRK2 is a multi-domain protein with both GTPase and kinase activities that has been shown to affect various cellular processes including protein homeostasis, however how PD mutations in LRRK2 may lead to accumulation of ubiquitinated protein aggregates remains unclear.A main cellular pathway to remove aggregated ubiquitinated proteins is aggrephagy: the histone deacetylase HDAC6 recognizes ubiquitinated misfolded proteins and recruits them to the molecular motor cytoplasmic dynein which transports them to the perinuclear region where they are trapped in aggresomes that are subsequently removed by macroautophagy.Here we identified HDAC6 as a novel LRRK2 substrate and show that LRRK2 regulates HDAC6-dependent aggresome formation. LRRK2 directly interacted with the HDAC6 deacetylase domains via its Roc domain and phosphorylated HDAC6 on serine-22. Serine-22 phosphorylation of HDAC6 enhanced its interaction with cytoplasmic dynein and stimulated recruitment of ubiquitinated proteins to aggresomes. Knockdown or knockout of LRRK2 impaired HDAC6-mediated aggresome formation. PD mutant LRRK2 G2019S showed reduced interaction with HDAC6 and did not support aggresome formation to the same extend as wild type LRRK2. This was recapitulated in LRRK2 G2019S patient-derived iAstrocytes that showed an aggresome formation defect.In conclusion our data reveal HDAC6 as a target of LRRK2 and suggest that deregulation of HDAC6-mediated aggresome formation and aggrephagy could contribute to the pathology of PD.