Dynein light chain 1 is required for autophagy, protein clearance, and cell death in Drosophila.
Autophagy is a catabolic pathway that is important for turnover of long-lived proteins and organelles, and has been implicated in cell survival, tumor progression, protection from infection, neurodegeneration, and cell death. Autophagy and caspases are required for type II autophagic cell death of Drosophila larval salivary glands during development, but the mechanisms that regulate these degradation pathways are not understood. We conducted a forward genetic screen for genes that are required for salivary gland cell death, and here we describe the identification of Drosophila dynein light chain 1 (ddlc1) as a gene that is required for type II cell death. Autophagy is attenuated in ddlc1 mutants, but caspases are active in these cells. ddlc1 mutant salivary glands develop large fibrillar protein inclusions that stain positive for amyloid-specific dyes and ubiquitin. Ectopic expression of Atg1 is sufficient to induce autophagy, clear protein inclusions, and rescue degradation of ddlc1 mutant salivary glands. Furthermore, ddlc1 mutant larvae have decreased motility, and mutations in ddlc1 enhance the impairment of motility that is observed in a Drosophila model of neurodegenerative disease. Significantly, this decrease in larval motility is associated with decreased clearance of protein with polyglutamine expansion, the accumulation of p62 in neurons and muscles, and fewer synaptic boutons. These results indicate that DDLC1 is required for protein clearance by autophagy that is associated with autophagic cell death and neurodegeneration.
Batlevi
Yakup
Y
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Martin
Damali N
DN
Pandey
Udai Bhan
UB
Simon
Claudio R
CR
Powers
Christine M
CM
Taylor
J Paul
JP
Baehrecke
Eric H
EH
D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy / Q000235:genetics*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D017124:Conserved Sequence; D003433:Crosses, Genetic; D056445:Cytoplasmic Dyneins / Q000235:genetics*; D004247:DNA / Q000235:genetics; D004330:Drosophila / Q000166:cytology / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics*; D020287:In Situ Nick-End Labeling; D007814:Larva / Q000235:genetics; D016254:Mutagenesis, Insertional; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics; D011679:Pupa / Q000235:genetics; D012469:Salivary Glands / Q000473:pathology / Q000502:physiology; D013569:Synapses / Q000502:physiology
D029721:Drosophila Proteins; D004247:DNA; D020169:Caspases; C430717:Dlc90F protein, Drosophila; D056445:Cytoplasmic Dyneins