title: Differential expression, distinct localization and opposite effect on Golgi structure and cell differentiation by a novel splice variant of human PRMT5.
abstract: Alternative splicing contributes greatly to the proteomic diversity of metazoans. Protein arginine methyltransferase 5 (PRMT5) methylates arginines of Golgi components and other factors exerting diverse effects on cell growth/differentiation, but the underlying molecular basis for its subcellular distribution and diverse roles has not been fully understood. Here we show the detailed properties of an evolutionarily emerged splice variant of human PRMT5 (PRMT5S) that is distinct from the original isoform (PRMT5L). The isoforms are differentially expressed among mammalian cells and tissues. The PRMT5S is distributed all over the cell but PRMT5L mainly colocalizes with Giantin, a Golgi marker. PRMT5 knockdown led to an enlarged Giantin pattern, which was prevented by the expression of either isoform. Rescuing PRMT5S also increased the percentage of cells with an interphase Giantin pattern compacted at one end of the nucleus, consistent with its cell cycle-arresting effect, while rescuing PRMT5L increased that of the mitotic Giantin patterns of dynamically fragmented structures. Moreover, the isoforms are differentially expressed during neuronal or dendritic cell differentiation, and their ectopic expression showed an opposite effect on dendritic cell differentiation. Furthermore, besides their differential regulation of gene expression, both isoforms also similarly regulate over a thousand genes particularly those involved in apoptosis and differentiation. Taking these properties together, we propose that their differential expression and subcellular localization contribute to spatial and temporal regulation of arginine methylation and gene expression to exert different effects. The novel PRMT5S likely contributes to the observed diverse effects of PRMT5 in cells.
authors.affiliation: Department of Physiology & Pathophysiology, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Sohail
authors.affiliation: Department of Immunology, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
authors.forename: Manli
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Litchfield
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Canada.
authors.forename: Lisheng
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Immunology, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
authors.forename: Sam
authors.initials: S
authors.lastname: Kung
authors.affiliation: Department of Physiology & Pathophysiology, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; Department of Biochemistry & Medical Genetics, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada. Electronic address: xiej@umanitoba.ca.
authors.forename: Jiuyong
authors.initials: J
authors.lastname: Xie
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006056:Golgi Apparatus / Q000201:enzymology* / Q000235:genetics; D000077614:Golgi Matrix Proteins; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D011484:Protein-Arginine N-Methyltransferases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000077614:Golgi Matrix Proteins; D008565:Membrane Proteins; C087574:macrogolgin; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases
keywords: Alternative splicing; Cell cycle; Dendritic cell; Giantin; Golgi structure; PRMT5