Ack kinase regulates CTP synthase filaments during Drosophila oogenesis

Abstract

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 DA ck, 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 DA ck or lacking DA ck 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 DA ck may regulate CTP synthase activity. These findings highlight an unexpected function for DA ck and provide insight into a novel pathway for the developmental control of an essential metabolic pathway governing nucleotide biosynthesis. image DA ck kinase is shown to localize to CTP synthase ( CTPS ) filaments in germ cells of the Drosophila ovary. DA ck catalytic activity is required for normal CTPS filament morphology and CTP ‐dependent processes such as RNA production, plasma membrane integrity and fertility. DA ck localizes to cytoplasmic assemblies of the nucleotide biosynthetic enzyme CTPS . Catalytically active CTPS localizes to filaments. Flies deficient in DA ck catalytic activity have morphologically abnormal CTPS filaments, reduced RNA levels, membrane phospholipid defects and reduced fertility.