A Cullin1-based SCF E3 ubiquitin ligase targets the InR/PI3K/TOR pathway to regulate neuronal pruning.
Pruning that selectively eliminates unnecessary axons/dendrites is crucial for sculpting the nervous system during development. During Drosophila metamorphosis, dendrite arborization neurons, ddaCs, selectively prune their larval dendrites in response to the steroid hormone ecdysone, whereas mushroom body γ neurons specifically eliminate their axon branches within dorsal and medial lobes. However, it is unknown which E3 ligase directs these two modes of pruning. Here, we identified a conserved SCF E3 ubiquitin ligase that plays a critical role in pruning of both ddaC dendrites and mushroom body γ axons. The SCF E3 ligase consists of four core components Cullin1/Roc1a/SkpA/Slimb and promotes ddaC dendrite pruning downstream of EcR-B1 and Sox14, but independently of Mical. Moreover, we demonstrate that the Cullin1-based E3 ligase facilitates ddaC dendrite pruning primarily through inactivation of the InR/PI3K/TOR pathway. We show that the F-box protein Slimb forms a complex with Akt, an activator of the InR/PI3K/TOR pathway, and promotes Akt ubiquitination. Activation of the InR/PI3K/TOR pathway is sufficient to inhibit ddaC dendrite pruning. Thus, our findings provide a novel link between the E3 ligase and the InR/PI3K/TOR pathway during dendrite pruning.
Temasek Life Sciences Laboratory and Department of Biological Sciences, National University of Singapore, Singapore ; Graduate School for Integrated Sciences and Engineering, Centre for Life Sciences, National University of Singapore (NUS), Singapore.
Jack Jing Lin
JJ
Wong
Song
S
Li
Edwin Kok Hao
EK
Lim
Yan
Y
Wang
Cheng
C
Wang
Heng
H
Zhang
Daniel
D
Kirilly
Chunlai
C
Wu
Yih-Cherng
YC
Liou
Hongyan
H
Wang
Fengwei
F
Yu
D000818:Animals; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D003712:Dendrites / Q000378:metabolism; D004330:Drosophila / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004440:Ecdysone / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D008675:Metamorphosis, Biological; D024521:Mushroom Bodies / Q000294:innervation; D009420:Nervous System / Q000196:embryology*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D055749:SOXB2 Transcription Factors / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D004440:Ecdysone; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases; D044843:SKP Cullin F-Box Protein Ligases; D055749:SOXB2 Transcription Factors; D058570:TOR Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; C115373:DNA supercoiling factor, Drosophila; C496247:MICAL protein, Drosophila; C498870:Roc1a protein, Drosophila; C434749:SkpA protein, Drosophila; C492174:Sox14 protein, Drosophila; C110233:slmb protein, Drosophila; C416303:target of rapamycin protein, Drosophila; C094982:InR protein, Drosophila