title: HDAC8 Catalyzes the Hydrolysis of Long Chain Fatty Acyl Lysine.
abstract: The histone deacetylase (HDAC) family regulates many biological pathways through the deacetylation of lysine residues on histone and nonhistone proteins. Mammals have 18 HDACs that are classified into four classes. Class I, II, and IV are zinc-dependent, while class III is nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylase or sirtuins. HDAC8, a class I HDAC family member, has been shown to have low deacetylation activity compared to other HDACs in vitro. Recent studies showed that several sirtuins, with low deacetylase activities, can actually hydrolyze other acyl lysine modifications more efficiently. Inspired by this, we tested the activity of HDAC8 using a variety of different acyl lysine peptides. Screening a panel of peptides with different acyl lysine modifications, we found that HDAC8 can catalyze the removal of acyl groups with 2-16 carbons from lysine 9 of the histone H3 peptide (H3K9). Interestingly, the catalytic efficiencies (kcat/Km) of HDAC8 on octanoyl, dodecanoyl, and myristoyl lysine are several-fold better than that on acetyl lysine. The increased catalytic efficiencies of HDAC8 on larger fatty acyl groups are due to the much lower Kmvalues. T-cell leukemia Jurkat cells treated with a HDAC8 specific inhibitor, PCI-34051, exhibited an increase in global fatty acylation compared to control treatment. Thus, the de-fatty-acylation activity of HDAC8 is likely physiologically relevant. This is the first report of a zinc-dependent HDAC with de-fatty-acylation activity, and identification of HDAC8 de-fatty-acylation targets will help to further understand the function of HDAC8 and protein lysine fatty acylation.
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853, United States.
authors.forename: Pornpun
authors.initials: P
authors.lastname: Aramsangtienchai
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853, United States.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Spiegelman
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853, United States.
authors.forename: Seth P
authors.initials: SP
authors.lastname: Miller
authors.affiliation: Ben May Department of Cancer Research, The University of Chicago , Chicago, Illinois 60637, United States.
authors.forename: Lunzhi
authors.initials: L
authors.lastname: Dai
authors.affiliation: Ben May Department of Cancer Research, The University of Chicago , Chicago, Illinois 60637, United States.
authors.forename: Yingming
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853, United States.|Howard Hughes Medical Institute, Cornell University , Ithaca, New York 14853, United States.
authors.forename: Hening
authors.initials: H
authors.lastname: Lin
mesh_terms: D000595:Amino Acid Sequence; D055162:Biocatalysis; D005227:Fatty Acids / Q000378:metabolism*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006868:Hydrolysis; D008239:Lysine / Q000378:metabolism*; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases; D008239:Lysine