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NDST3 deacetylates α-tubulin and suppresses V-ATPase assembly and lysosomal acidification
The EMBO Journal ( IF 11.4 ) Pub Date : 2021-08-25 , DOI: 10.15252/embj.2020107204
Qing Tang 1, 2 , Mingming Liu 1, 2 , Yang Liu 1, 2 , Ran-Der Hwang 1, 2 , Tao Zhang 1, 2 , Jiou Wang 1, 2
Affiliation  

Lysosomes are key organelles maintaining cellular homeostasis in health and disease. Here, we report the identification of N-deacetylase and N-sulfotransferase 3 (NDST3) as a potent regulator of lysosomal functions through an unbiased genetic screen. NDST3 constitutes a new member of the histone deacetylase (HDAC) family and catalyzes the deacetylation of α-tubulin. Loss of NDST3 promotes assembly of the V-ATPase holoenzyme on the lysosomal membrane and thereby increases the acidification of the organelle. NDST3 is downregulated in tissues and cells from patients carrying the C9orf72 hexanucleotide repeat expansion linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Deficiency in C9orf72 decreases the level of NDST3, and downregulation of NDST3 exacerbates the proteotoxicity of poly-dipeptides generated from the C9orf72 hexanucleotide repeats. These results demonstrate a previously unknown regulatory mechanism through which microtubule acetylation regulates lysosomal activities and suggest that NDST3 could be targeted to modulate microtubule and lysosomal functions in relevant diseases.

中文翻译:

NDST3 使 α-微管蛋白去乙酰化并抑制 V-ATPase 组装和溶酶体酸化

溶酶体是在健康和疾病中维持细胞稳态的关键细胞器。在这里,我们通过无偏见的遗传筛选报告了 N-脱乙酰酶和 N-磺基转移酶 3 (NDST3) 作为溶酶体功能的有效调节剂的鉴定。NDST3 是组蛋白脱乙酰酶 (HDAC) 家族的新成员,可催化 α-微管蛋白的脱乙酰化。NDST3 的缺失促进了 V-ATPase 全酶在溶酶体膜上的组装,从而增加了细胞器的酸化。NDST3 在携带 C9orf72 六核苷酸重复序列扩增的患者的组织和细胞中下调,这些序列与神经退行性疾病肌萎缩侧索硬化 (ALS) 和额颞叶痴呆 (FTD) 相关。C9orf72 的缺乏会降低 NDST3 的水平,NDST3 的下调加剧了由 C9orf72 六核苷酸重复序列产生的聚二肽的蛋白毒性。这些结果证明了一种以前未知的调节机制,微管乙酰化通过该机制调节溶酶体活性,并表明 NDST3 可以靶向调节相关疾病中的微管和溶酶体功能。
更新日期:2021-10-04
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