NDST3 deacetylates α-tubulin and suppresses V-ATPase assembly and lysosomal acidification

Qing Tang, Mingming Liu, Yang Liu, Ran Der Hwang, Tao Zhang, Jiou Wang

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbere107204
JournalEMBO Journal
Issue number19
StatePublished - Oct 1 2021


  • N-deacetylase and N-sulfotransferase 3
  • V-ATPase assembly
  • amyotrophic lateral sclerosis
  • lysosomal acidification
  • microtubule acetylation

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology


Dive into the research topics of 'NDST3 deacetylates α-tubulin and suppresses V-ATPase assembly and lysosomal acidification'. Together they form a unique fingerprint.

Cite this