title: Acyl-CoA:lysophosphatidylcholine acyltransferase I (Lpcat1) catalyzes histone protein O-palmitoylation to regulate mRNA synthesis.
abstract: The enzyme acyl-CoA:lysophosphatidylcholine acyltransferase (Lpcat1) is a critical cytosolic enzyme needed for lung surfactant synthesis that catalyzes an acyltransferase reaction by adding a palmitate to the sn-2 position of lysophospholipids. Here we report that histone H4 protein is subject to palmitoylation catalyzed by Lpcat1 in a calcium-regulated manner. Cytosolic Lpcat1 was observed to shift into the nucleus in lung epithelia in response to exogenous Ca(2+). Nuclear Lpcat1 colocalizes with and binds to histone H4, where it catalyzes histone H4 palmitoylation. Mutagenesis studies demonstrated that Ser(47) within histone H4 serves as a putative acceptor site, indicative of Lpcat1-mediated O-palmitoylation. Lpcat1 knockdown or expression of a histone H4 Ser(47A) mutant protein in cells decreased cellular mRNA synthesis. These findings provide the first evidence of a protein substrate for Lpcat1 and reveal that histone lipidation may occur through its O-palmitoylation as a novel post-translational modification. This epigenetic modification regulates global gene transcriptional activity.
authors.affiliation: Department of Medicine, the Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. zouc@upmc.edu
authors.forename: Chunbin
authors.initials: C
authors.lastname: Zou
authors.forename: Bryon M
authors.initials: BM
authors.lastname: Ellis
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Smith
authors.forename: Bill B
authors.initials: BB
authors.lastname: Chen
authors.forename: Yutong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mallampalli
mesh_terms: D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus / Q000502:physiology; D019943:Amino Acid Substitution; D002384:Catalysis; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000502:physiology; D055785:Gene Knockdown Techniques; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D054878:Lipoylation / Q000502:physiology*; D020125:Mutation, Missense; D019308:Palmitic Acid / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D006657:Histones; D012333:RNA, Messenger; D019308:Palmitic Acid; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C526203:Lpcat1 protein, mouse