title: Acinus integrates AKT1 and subapoptotic caspase activities to regulate basal autophagy.
abstract: How cellular stresses up-regulate autophagy is not fully understood. One potential regulator is the Drosophila melanogaster protein Acinus (Acn), which is necessary for autophagy induction and triggers excess autophagy when overexpressed. We show that cell type-specific regulation of Acn depends on proteolysis by the caspase Dcp-1. Basal Dcp-1 activity in developing photoreceptors is sufficient for this cleavage without a need for apoptosis to elevate caspase activity. On the other hand, Acn was stabilized by loss of Dcp-1 function or by the presence of a mutation in Acn that eliminates its conserved caspase cleavage site. Acn stability also was regulated by AKT1-mediated phosphorylation. Flies that expressed stabilized forms of Acn, either the phosphomimetic Acn(S641,731D) or the caspase-resistant Acn(D527A), exhibited enhanced basal autophagy. Physiologically, these flies showed improvements in processes known to be autophagy dependent, including increased starvation resistance, reduced Huntingtin-induced neurodegeneration, and prolonged life span. These data indicate that AKT1 and caspase-dependent regulation of Acn stability adjusts basal autophagy levels.
authors.affiliation: Department of Neuroscience and Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Nilay
authors.initials: N
authors.lastname: Nandi
authors.affiliation: Department of Neuroscience and Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Lauren K
authors.initials: LK
authors.lastname: Tyra
authors.affiliation: Department of Neuroscience and Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Drew
authors.initials: D
authors.lastname: Stenesen
authors.affiliation: Department of Neuroscience and Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390 Department of Neuroscience and Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390 helmut.kramer@utsouthwestern.edu.
authors.forename: Helmut
authors.initials: H
authors.lastname: Krämer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D001665:Binding Sites; D020169:Caspases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017124:Conserved Sequence; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D008136:Longevity / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016415:Sequence Alignment; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C550148:Acn protein, Drosophila; D029721:Drosophila Proteins; D014157:Transcription Factors; C494917:Akt1 protein, Drosophila; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; C103568:Dcp-1 protein, Drosophila