title: Gradients of a ubiquitin E3 ligase inhibitor and a caspase inhibitor determine differentiation or death in spermatids.
abstract: Caspases are executioners of apoptosis but also participate in a variety of vital cellular processes. Here, we identified Soti, an inhibitor of the Cullin-3-based E3 ubiquitin ligase complex required for caspase activation during Drosophila spermatid terminal differentiation (individualization). We further provide evidence that the giant inhibitor of apoptosis-like protein dBruce is a target for the Cullin-3-based complex, and that Soti competes with dBruce for binding to Klhl10, the E3 substrate recruitment subunit. We then demonstrate that Soti is expressed in a subcellular gradient within spermatids and in turn promotes proper formation of a similar dBruce gradient. Consequently, caspase activation occurs in an inverse graded fashion, such that the regions of the developing spermatid that are the last to individualize experience the lowest levels of activated caspases. These findings elucidate how the spatial regulation of caspase activation can permit caspase-dependent differentiation while preventing full-blown apoptosis.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Kaplan
authors.forename: Liron
authors.initials: L
authors.lastname: Gibbs-Bar
authors.forename: Yossi
authors.initials: Y
authors.lastname: Kalifa
authors.forename: Yael
authors.initials: Y
authors.lastname: Feinstein-Rotkopf
authors.forename: Eli
authors.initials: E
authors.lastname: Arama
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D061945:Caspase Inhibitors; D002454:Cell Differentiation / Q000502:physiology; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D017344:Genes, Insect; D008297:Male; D008954:Models, Biological; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D013087:Spermatids / Q000166:cytology* / Q000378:metabolism*; D013091:Spermatogenesis / Q000235:genetics / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors*
chemical_list: C470733:Bruce protein, Drosophila; D061945:Caspase Inhibitors; C503647:Cul3 protein, Drosophila; D044842:Cullin Proteins; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D044767:Ubiquitin-Protein Ligases