PDF(Pubmed)
Abstract：
The six subunits (Elp1 to Elp6) Elongator complex promotes specific uridine modifications in tRNA\'s wobble site. Moreover, this complex has been indirectly involved in the regulation of α-tubulin acetylation in microtubules (MTs) via the stabilization of ATP-Citrate Lyase (Acly), the main cytosolic source of acetyl-CoA production in cells, a key substrate used for global protein acetylation. Here, we report additional evidence that Elongator activity is important for proper cytoskeleton remodeling as cells lacking expression of Elp1 show morphology impairment; including distinct neurite process formation and disorganization and instability of MTs. Here, we show that loss of Elongator results in a reduction of expression of the microtubule associated protein Tau (MAPT). Tau, is a well-known key MT regulator in neurons whose lysines can be competitively acetylated or ubiquitylated. Therefore, we tested whether Tau is an indirect acetylation target of Elongator. We found that a reduction of Elongator activity leads to a decrease of lysine acetylation on Tau that favors its proteasomal degradation. This phenotype was prevented by using selective deacetylase or proteasomal inhibitors. Moreover, our data demonstrate that Acly\'s activity regulates the mechanism underlying Tau mediated neurite morphology defects found in Elp1 KD since both Tau levels and neurites morphology are restored due to Acly overexpression. This suggests a possible involvement of both Tau and Acly dysfunction in Familial Dysautonomia (FD), which is an autosomal recessive peripheral neuropathy caused by mutation in the ELP1 gene that severely affects Elp1 expression levels in the nervous system in FD patients in a similar way as found previously in Elp1 KD neuroblastoma cells.
摘要：
六个亚基（Elp1至Elp6）延长复合物促进tRNA摆动位点的特定尿苷修饰。此外，该复合物通过稳定ATP-柠檬酸裂解酶（Acly）间接参与微管（MT）中α-微管蛋白乙酰化的调节，细胞中乙酰辅酶A产生的主要胞质来源，用于整体蛋白质乙酰化的关键底物。这里,我们报告了额外的证据表明,延长体活性对于正常的细胞骨架重塑是重要的,因为缺乏Elp1表达的细胞表现出形态学损伤;包括明显的神经突过程形成和MT的解体和不稳定。这里,我们显示延长体的缺失导致微管相关蛋白Tau(MAPT)的表达减少。Tau,是神经元中众所周知的关键MT调节剂，其赖氨酸可以竞争性乙酰化或泛素化。因此,我们测试了Tau是否是延伸因子的间接乙酰化目标。我们发现，延长子活性的降低导致Tau上赖氨酸乙酰化的减少，这有利于其蛋白酶体降解。通过使用选择性脱乙酰酶或蛋白酶体抑制剂来预防这种表型。此外，我们的数据表明，Acly的活性调节了在Elp1KD中发现的Tau介导的神经突形态缺陷的潜在机制，因为Tau水平和神经突形态均因Acly过表达而恢复。这表明Tau和Acly功能障碍可能参与家族性自主神经失调（FD），这是由ELP1基因突变引起的常染色体隐性遗传周围神经病变，严重影响FD患者神经系统中Elp1的表达水平，其方式与以前在Elp1KD神经母细胞瘤细胞中发现的相似。
