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Autophagy. 2018;14(6):1043-1059. doi: 10.1080/15548627.2018.1447290. Epub 2018 Jul 30.

Importance of TFEB acetylation in control of its transcriptional activity and lysosomal function in response to histone deacetylase inhibitors.

Author information

1
a Department of Oncology , Clinical Research Institute, Key Laboratory of Tumor Molecular Diagnosis and Individual Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College , Hangzhou , China.
2
b Department of Physiology , Yong Loo Lin School of Medicine, National University of Singapore , Singapore.
3
c Division of Chemical Biology and BioTechnology , School of Biological Sciences, Nanyang Technological University , Singapore.
4
d Department of Applied Biology and Chemical Technology , The Hong Kong Polytechnic University, Hung Hom , Kowloon , Hong Kong , China.
5
e Life Sciences Program, Faculty of Arts and Sciences , University of Toronto , Toronto , Canada.
6
f Department of Biological Sciences , National University of Singapore , Singapore.
7
g NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore , Singapore.

Abstract

TFEB (transcription factor EB) is a master regulator of lysosomal biogenesis, function and autophagy. The transcriptional activity of TFEB is mainly controlled by its phosphorylation status mediated by the MTOR (mechanistic target of rapamycin [serine/threonine kinase]) complex 1 (MTORC1). At present, little is known whether other forms of posttranslational modifications (PTMs) such as acetylation also affects is transcriptional activity. In this study, we first observed that a well-established histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) activated lysosomal function in human cancer cells, a process independent of the MTORC1 pathway. Second, SAHA treatment activated TFEB transcriptional activity, as evidenced by increased TFEB luciferase activity and expression of its target genes. Third and more importantly, we observed the enhanced TFEB acetylation in SAHA-treated cells, with identification of 4 acetylation sites. Mutation of these 4 sites markedly diminished TFEB transcriptional activity and lysosomal function induced by SAHA. Finally, we found that TFEB acetylation was functionally implicated in SAHA-mediated autophagy and cell death in cancer cells. Taken together, our results demonstrate that TFEB acetylation is a novel form of PTMs in TFEB that plays an important role in determining its transcriptional activity, lysosomal function and autophagy in cancer cells.

ABBREVIATIONS:

ACAT1: acetyl-coenzyme A acetyltransferase 1; AHA: L-azidohomoalanine; AO: acidic orange; ATG: autophagy related; CLEAR: Coordinated Lysosomal Expression and Regulation; CQ: chloroquine; CTSB: cathepsin B; HATs: histone acetyltransferases; HDACIs: HDACs inhibitors; HDACs: histone deacetylases; IP: immunoprecipitation; MEFs: mouse embryonic fibroblasts; MS: mass spectrometry; MTOR: mechanistic target of rapamycin (serine/threonine kinase); MTORC1: mechanistic target of rapamycin (serine/threonine kinase) complex 1; PTMs: posttranslational modifications; SAHA: suberoylanilidehydroxamic acid; TFEB: transcription factor EB.

KEYWORDS:

Acetylation; TFEB; autophagy; histone deacetylase inhibitors; lysosome

PMID:
30059277
PMCID:
PMC6103407
[Available on 2019-07-30]
DOI:
10.1080/15548627.2018.1447290

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