title: The histone methyltransferase Wbp7 controls macrophage function through GPI glycolipid anchor synthesis.
abstract: Histone methyltransferases catalyze site-specific deposition of methyl groups, enabling recruitment of transcriptional regulators. In mammals, trimethylation of lysine 4 in histone H3, a modification localized at the transcription start sites of active genes, is catalyzed by six enzymes (SET1a and SET1b, MLL1-MLL4) whose specific functions are largely unknown. By using a genomic approach, we found that in macrophages, MLL4 (also known as Wbp7) was required for the expression of Pigp, an essential component of the GPI-GlcNAc transferase, the enzyme catalyzing the first step of glycosylphosphatidylinositol (GPI) anchor synthesis. Impaired Pigp expression in Wbp7(-/-) macrophages abolished GPI anchor-dependent loading of proteins on the cell membrane. Consistently, loss of GPI-anchored CD14, the coreceptor for lipopolysaccharide (LPS) and other bacterial molecules, markedly attenuated LPS-triggered intracellular signals and gene expression changes. These data link a histone-modifying enzyme to a biosynthetic pathway and indicate a specialized biological role for Wbp7 in macrophage function and antimicrobial response.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: Liv
authors.initials: L
authors.lastname: Austenaa
authors.forename: Iros
authors.initials: I
authors.lastname: Barozzi
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Chronowska
authors.forename: Alberto
authors.initials: A
authors.lastname: Termanini
authors.forename: Renato
authors.initials: R
authors.lastname: Ostuni
authors.forename: Elena
authors.initials: E
authors.lastname: Prosperini
authors.forename: A Francis
authors.initials: AF
authors.lastname: Stewart
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Testa
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Natoli
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D017261:Glycosylphosphatidylinositols / Q000096:biosynthesis / Q000378:metabolism*; D006602:Hexosyltransferases / Q000096:biosynthesis; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051788:Myeloid-Lymphoid Leukemia Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C485893:Dscr5 protein, mouse; D017261:Glycosylphosphatidylinositols; D006657:Histones; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C510860:Kmt2d protein, mouse; D006602:Hexosyltransferases