Ack kinase regulates CTP synthase filaments during Drosophila oogenesis

• Published in: EMBO reports 2014-11, Vol.15 (11), p.1184-1191
• Main Authors: Strochlic, Todd I, Stavrides, Kevin P, Thomas, Sam V, Nicolas, Emmanuelle, O'Reilly, Alana M, Peterson, Jeffrey R
• Format: Article
• Language: English
• Subjects: Ack; Animals; Biosynthesis; Carbon-Nitrogen Ligases - genetics; Carbon-Nitrogen Ligases - metabolism; CTP synthase; cytoophidia; Drosophila - genetics; Drosophila - metabolism; Drosophila - physiology; Drosophila oogenesis; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; EMBO11; Enzymes; Female; Fertility; Insects; Kinases; Mammals; Morphology; Oogenesis; Ovary - metabolism; Protein Transport; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; RNA - metabolism; Scientific Report; Scientific Reports; Yeasts
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201438688

The enzyme CTP synthase (CTPS) dynamically assembles into macromolecular filaments in bacteria, yeast, Drosophila , and mammalian cells, but the role of this morphological reorganization in regulating CTPS activity is controversial. During Drosophila oogenesis, CTPS filaments are transiently apparent in ovarian germline cells during a period of intense genomic endoreplication and stockpiling of ribosomal RNA. Here, we demonstrate that CTPS filaments are catalytically active and that their assembly is regulated by the non‐receptor tyrosine kinase DAck, the Drosophila homologue of mammalian Ack1 (activated cdc42‐associated kinase 1), which we find also localizes to CTPS filaments. Egg chambers from flies deficient in DAck or lacking DAck catalytic activity exhibit disrupted CTPS filament architecture and morphological defects that correlate with reduced fertility. Furthermore, ovaries from these flies exhibit reduced levels of total RNA, suggesting that DAck may regulate CTP synthase activity. These findings highlight an unexpected function for DAck and provide insight into a novel pathway for the developmental control of an essential metabolic pathway governing nucleotide biosynthesis. Synopsis DAck kinase is shown to localize to CTP synthase (CTPS) filaments in germ cells of the Drosophila ovary. DAck catalytic activity is required for normal CTPS filament morphology and CTP‐dependent processes such as RNA production, plasma membrane integrity and fertility. DAck localizes to cytoplasmic assemblies of the nucleotide biosynthetic enzyme CTPS. Catalytically active CTPS localizes to filaments. Flies deficient in DAck catalytic activity have morphologically abnormal CTPS filaments, reduced RNA levels, membrane phospholipid defects and reduced fertility. Graphical Abstract DAck kinase is shown to localize to CTP synthase (CTPS) filaments in germ cells of the Drosophila ovary. DAck catalytic activity is required for normal CTPS filament morphology and CTP‐dependent processes such as RNA production, plasma membrane integrity and fertility.