HDAC6 Substrate Discovery Using Proteomics-Based Substrate Trapping: HDAC6 Deacetylates PRMT5 to Influence Methyltransferase Activity

Histone deacetylase 6 (HDAC6) is upregulated in a variety of tumor cell lines and has been linked to many cellular processes, such as cell signaling, protein degradation, cell survival, and cell motility. HDAC6 is an enzyme that deacetylates the acetyllysine residues of protein substrates, and the d...

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Bibliographic Details
Published in:ACS chemical biology 2021-08, Vol.16 (8), p.1435-1444
Main Authors: Gomes, Inosha D, Ariyaratne, Udana V, Pflum, Mary Kay H
Format: Article
Language:English
Subjects:
Acetylation
Catalytic Domain - genetics
DNA Helicases - metabolism
HEK293 Cells
Histone Deacetylase 6 - chemistry
Histone Deacetylase 6 - genetics
Histone Deacetylase 6 - metabolism
Humans
Mutation
Poly-ADP-Ribose Binding Proteins - metabolism
Protein-Arginine N-Methyltransferases - chemistry
Protein-Arginine N-Methyltransferases - metabolism
Proteomics - methods
RNA Helicases - metabolism
RNA Recognition Motif Proteins - metabolism
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Summary:Histone deacetylase 6 (HDAC6) is upregulated in a variety of tumor cell lines and has been linked to many cellular processes, such as cell signaling, protein degradation, cell survival, and cell motility. HDAC6 is an enzyme that deacetylates the acetyllysine residues of protein substrates, and the discovery of HDAC6 substrates, including tubulin, has revealed many roles of HDAC6 in cell biology. Unfortunately, among the wide variety of acetylated proteins in the cell, only a few are verified as HDAC6 substrates, which limits the full characterization of HDAC6 cellular functions. Substrate trapping mutants were recently established as a tool to discover unanticipated substrates of histone deacetylase 1 (HDAC1). In this study, we applied the trapping approach to identify potential HDAC6 substrates. Among the high confidence protein hits after trapping, protein arginine methyl transferase 5 (PRMT5) was successfully validated as a novel HDAC6 substrate. PRMT5 acetylation enhanced its methyltransferase activity and symmetrical dimethylation of downstream substrates, revealing possible crosstalk between acetylation and methylation. Substrate trapping represents a powerful, systematic, and unbiased approach to discover substrates of HDAC6.
ISSN:1554-8929
1554-8937
DOI:10.1021/acschembio.1c00303