Persephone/Spätzle pathogen sensors mediate the activation of Toll receptor signaling in response to endogenous danger signals in apoptosis-deficient Drosophila.
Apoptosis is an evolutionarily conserved mechanism that removes damaged or unwanted cells, effectively maintaining cellular homeostasis. It has long been suggested that a deficiency in this type of naturally occurring cell death could potentially lead to necrosis, resulting in the release of endogenous immunogenic molecules such as damage-associated molecular patterns (DAMPs) and a noninfectious inflammatory response. However, the details about how danger signals from apoptosis-deficient cells are detected and translated to an immune response are largely unknown. In this study, we found that Drosophila mutants deficient for Dronc, the key initiator caspase required for apoptosis, produced the active form of the endogenous Toll ligand Spätzle (Spz). We speculated that, as a system for sensing potential DAMPs in the hemolymph, the dronc mutants constitutively activate a proteolytic cascade that leads to Spz proteolytic processing. We demonstrated that Toll signaling activation required the action of Persephone, a CLIP domain serine protease that usually reacts to microbial proteolytic activities. Our findings show that the Persephone proteolytic cascade plays a crucial role in mediating DAMP-induced systemic responses in apoptosis-deficient Drosophila mutants.
From the Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Ming
M
Ming
Fumiaki
F
Obata
Erina
E
Kuranaga
Masayuki
M
Miura
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006434:Hemocytes / Q000378:metabolism; D006458:Hemolymph / Q000378:metabolism; D007113:Immunity, Innate; D007150:Immunohistochemistry; D008024:Ligands; D009154:Mutation; D009336:Necrosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*
D029721:Drosophila Proteins; D008024:Ligands; D051193:Toll-Like Receptors; C086179:spz protein, Drosophila; D049452:Green Fluorescent Proteins; C091227:DRS protein, Drosophila; D012697:Serine Endopeptidases; C460880:psh protein, Drosophila; D020169:Caspases; C118731:dronc protein, Drosophila
Apoptosis; Caspase; Damage-associated Molecular Patterns; Drosophila; Innate Immunity; Necrosis (Necrotic Death); Serine Protease; Stress Response; Toll Receptors