The COP9 Signalosome Promotes Degradation of Cyclin E during Early Drosophila Oogenesis

Abstract

The COP9 signalosome (CSN) is an eight-subunit complex that regulates multiple signaling and cell cycle pathways. Here we link the CSN to the degradation of Cyclin E, which promotes the G1-S transition in the cell cycle and then is rapidly degraded by the ubiquitin-proteasome pathway. Using CSN4 and CSN5/Jab1 mutants, we show that the CSN acts during Drosophila oogenesis to remove Nedd8 from Cullin1, a subunit of the SCF ubiquitin ligase. Overexpression of Cyclin E causes similar defects as mutations in CSN or SCF(Ago) subunits: extra divisions or, in contrast, cell cycle arrest and polyploidy. Because the phenotypes are so similar and because CSN and Cyclin E mutations reciprocally suppress each other, Cyclin E appears to be the major target of the CSN during early oogenesis. Genetic interactions among CSN, SCF, and proteasome subunits further confirm CSN involvement in ubiquitin-mediated Cyclin E degradation.

Cyclin E and CDK-2 regulate proliferative cell fate and cell cycle progression in the C. elegans germline

“…In the adult hermaphrodite, CYE-1 levels and activity are high throughout proliferative zone cells, falling as they enter meiotic prophase. In Drosophila, cyclin E levels also fall as germ cells enter meiotic prophase, in large part due to SCF-mediated protein degradation (Doronkin et al, 2003;Narbonne-Reveau and Lilly, 2009). However, the precipitous decrease in cyclin E levels as cells enter meiotic prophase, in C. elegans and Drosophila, is presumably not the trigger for entry into meiosis because it occurs after meiotic S phase.…”

Nedd8 on cullin: building an expressway to protein destruction

“…In Arabidopsis, it was observed that a defect in the Nedd8 conjugation increased the level of unmodified CUL1 (Dharmasiri et al, 2003). However, in Drosophila, neddylated CUL1 was accumulated at high levels in CSN5/Jab1 mutants (Doronkin et al, 2003). Clearly, neddylation-deficient mutants will be useful in addressing whether Nedd8 modification has a role in the turn over of cullin proteins.…”

“…In support of this notion, recent studies using highly purified components showed that the CSN cleaved Nedd8 from hCUL1 catalytically . Additionally, in several organisms analysed (C. elegans, Drosophila and Arabidopsis), CSN activity is indispensable for deconjugation of Nedd8 from a number of tested cullins that include CUL1, CUL2 and CUL3 (Schwechheimer et al, 2001;Zhou et al, 2001;Yang et al, 2002;Doronkin et al, 2003;Pintard et al, 2003a). Surprisingly, requirement of the CSN for the deneddylation of spCUL4/Pcu4 might be different.…”

“…e . f Schwechheimer et al, 2001;Cope et al, 2002;Yang et al, 2002;Doronkin et al, 2003;Lykke-Andersen et al, 2003;Pintard et al, 2003a;Wu et al, 2003;Yan et al, 2003). g (Mendoza et al, 2003;Wu et al, 2003) Role of Nedd8 in proteolysis Z-Q Pan et al…”

“…However, in Arabidopsis, reduced CSN expression levels resulted in stabilization of SCF TIR1 substrate PSIAA6, and had decreased auxin-response, similar to loss of function mutants of SCF TIR1 (Schwechheimer et al, 2001). In Drosophila, the CSN appears to play a major role in early oogenesis by promoting the degradation of cyclin E (Doronkin et al, 2003). Also, in C. elegans, RNAi-mediated reduction of CSN function accumulated neddylated CUL3 and stabilized MEI-1 (Pintard et al, 2003a).…”