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Light-Dependent Interactions Between the Drosophila Circadian Clock Factors Cryptochrome, Jetlag, and Timeless

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Light-Dependent Interactions Between the Drosophila Circadian Clock Factors Cryptochrome, Jetlag, and Timeless View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Current Biology 19, 241–247, February 10, 2009 ª2009 Elsevier Ltd All rights reserved DOI 10.1016/j.cub.2008.12.042 Report Light-Dependent Interactions between the Drosophila Circadian Clock Factors Cryptochrome, Jetlag, and Timeless Nicolai Peschel,1 Ko Fan Chen,1 Gisela Szabo,1 by the ls-tim allele) as is the case in Veela flies [3]. The and Ralf Stanewsky1,* LL-rhythmic Veela phenotype resembles that of cry mutants 1School of Biological and Chemical Sciences [12, 13]. Also similar to cryb mutants, homozygous mutant Queen Mary University of London Veela flies accumulate abnormally high levels of Tim protein London E1 4NS in the light [3, 14]. Strikingly, both phenotypes are also United Kingdom observed in transheterozygous Veela/+; cryb/+ flies [3]. This strong genetic interaction between tim, jet, and cry prompted us to investigate a potential physical association between Summary Jetlag and Cry proteins in the yeast two-hybrid system (Y2H). In addition, the two different Timeless isoforms were Circadian clocks regulate daily fluctuations of many physio- also tested for interaction with Jetlag or Cryptochrome. In logical and behavioral aspects in life. They are synchronized agreement with an earlier study, light-dependent interaction with the environment via light or temperature cycles [1]. between both Tim proteins and Cry was observed, whereby Natural fluctuations of the day length (photoperiod) and S-Tim interacted more strongly with Cry as compared to temperature necessitate a daily reset of the circadian clock L-Tim (Figure 1A) [10]. Surprisingly, we also observed a striking on the molecular level. In Drosophila, the blue-light photore- light-dependent interaction between Cry and Jet (Figure 1B), ceptor Cryptochrome (Cry) mediates a rapid light-dependent but not between Tim and Jet (Figure 1A). Given that Tim and degradation of the clock protein Timeless (Tim) via the F box Jet do interact in S2 cells cotransfected with cry [2] and our protein Jetlag (Jet) and the proteasome, which initiates the finding that Jet interacts with Cry in yeast, an explanation for resetting of the molecular clock [2, 3]. Cry is also degraded the lack of Tim:Jet binding could be that Cry is essential for in the light but whereas the degradation of Tim is well char- this interaction. acterized [4–8], the mechanism for light-dependent degrada- The interaction between Jetc and Cry is significantly weaker tion of Cry is mostly unknown. Until now it was believed that compared with the wild-type protein (Figure 1B). Keeping in these two degradation pathways are distinct [4, 9]. Here we mind that the LRR is the binding region for the F box proteins’ reveal that Jetlag also interacts with Cry in a light-dependent substrate [15], this weaker association was expected. Addi- manner. After illumination, Jetlag induces massive degrada- tionally, we challenged Jet and Jetc with different Cry muta- tion of Cry, which can be prevented in vitro and in vivo by tions. In CryD the last 20 residues from the C terminus are adding Tim as an antagonist. We show that the affinity of missing, resulting in strong, light-independent interactions of Tim for Cry and Jetlag determines the sequential order of CryD with Tim [16]. We also could reveal a strong light- Tim and Cry degradation and thus reveal an intimate connec- independent interaction between Jet or Jetc and CryD tion between the light-dependent degradation of these two (Figure 1B). The Cryb protein does not interact with Jet or proteins by the same proteasomal pathway. Jetc (Figure 1B), correlating with its inability to bind to Tim in yeast [16]. Results and Discussion The strong biochemical and genetic interaction between cry and jet suggests that the Jet:Cry interaction is important The F box protein Jetlag (Jet) is involved in the resetting mech- in vivo and perhaps required for efficient light-induced Tim anism of the circadian clock [2, 3]. Jet is a putative component turnover. Given that we were unable to detect a direct interac- of a Skp1/Cullin/F-Box (SCF) E3 ubiquitin ligase complex that tion between Jet and Tim in yeast (Figure 1A), this implies that associates with Tim in a light-dependent fashion in an embry- binding of Cry to Tim could modify Tim in a way that it now can onic Drosophila cell line (S2) in the presence of Cry. This inter- bind Jet to induce degradation. Alternatively, the Jet:Cry action promotes the ubiquitination and degradation of Tim in complex binds to Tim (via Cry acting as a bridge), thereby cultured cells [2]. In nature, two Drosophila allelic variants of inducing Tim degradation. timeless can be found: one allele produces a 23 amino acid N-terminally shortened and more light-sensitive form of Tim Jetlag Binds to Cryptochrome and Timeless (s-tim), the other allele encodes both forms (ls-tim) [10, 11]. in Drosophila Cells At the molecular level, S-Tim’s enhanced light sensitivity is To distinguish between these two possibilities, we performed correlated with (and likely due to) enhanced binding to the CoIP experiments in an embryonic Drosophila cell line (S2). A circadian blue-light photoreceptor Cry ([10]; Figure 1A). full-length Jetlag protein fused to a HIS-tag (Jet-H) and untagged versions of Cry and Tim proteins were overex- Light-Dependent Interaction of the F Box Protein Jetlag pressed in S2 cells and immunoprecipitated with HIS antibody. with Cryptochrome in Yeast Cells were grown in darkness and exposed to light for 15 min The hypomorphic jetc mutation carries a single amino acid before performing the assay. As expected from the Y2H change in the leucine-rich repeat (LRR) region of Jet, which results, Cry also interacted with Jet-H in S2 cells (Figure 1C; causes flies to be rhythmic in constant light (LL), but only if see Figure S1 available online for specificity of Cry antibody). they express the less light-sensitive L-Tim protein (encoded Contrary to the Y2H results, Tim also interacts with Jet-H, without the addition of Cry (Figure 1C). When we simulta- neously expressed Tim and Cry in the presence of Jet-H, we *Correspondence: [email protected] could detect only minimal amounts of Tim protein in the input Current Biology Vol 19 No 3 242 Figure 1. Light-Dependent Interactions of Cryp- tochrome, Jetlag, and Timeless in Yeast and Drosophila S2 Cells (A) Yeast cells were grown in constant light at 30C. Binding strength is positively correlated with intensity of the blue staining [10]. (B) Yeast was grown in constant light (light) or under the same conditions, but wrapped in two layers of aluminum foil (dark). (C and D) pAc-Jet-His transfected S2 cells were used for immunoprecipitation with His antibody. Cells were transfected with plasmids as indi- cated, where + is transfected with the vector, 2 is not transfected. CoIPs were repeated three times with similar results. Before harvesting, the cells were exposed to light for 15 min in the absence (C) or presence (D) of MG-132 (added under red light 2 hr before cells were exposed to light). The asterisk marks unspecific background staining. Cry and Tim could not be precipitated by His antibodies in the absence of Jet-His (Supplemental Experimental Procedures). (E) The efficiency of ds-cry RNA treatment was determined by cotransfection of cry (pAc-cry, 1 mg) and different amount of ds-cry RNA. (F) CoIP experiment (performed as in [D]) of S2 cells transfected with pAc-Jet-His, pAc-l-tim, and either ds-cry RNA (2 mg) or ds-gfp RNA as control (2 mg). D should also be reduced by this treatment. CoIP experiments in the presence of MG-132 show that Jet:Tim interactions are dramatically reduced (but still detect- able) after dsRNA treatment (Figure 1F). This demonstrates that endogenous Cry levels are supporting Jet:Tim interaction E F observed in S2 cells. In cells transfected only with tim,we did observe a Jet:Tim interaction, but not a Jet:Cry interaction (Figures 1C and 1D, lanes 3 and 4). Even though the input levels of endogenous Cry and transfected Tim are very low, one would or CoIP fractions (Figure 1C, lanes 5 and 6). We speculated that expect to precipitate equal amounts of both proteins bound the low Tim levels were caused because we reconstituted a fully to Jet, if Cry would indeed form a bridge between Tim and functional light-sensitive clock-resetting protein complex. To Jet. This was not observed, and we repeatedly precipitated test this, we conducted the CoIP experiments also in the pres- only Tim, indicating the existence of Tim:Jet complexes that ence of the proteasomal inhibitor MG-132, which led to an over- are free of Cry. Our results therefore support a model in which all stabilization of the proteins and a clear demonstration of Cry modifies Tim, allowing Tim to interact with Jet after disso- Tim:Jet interactions in S2 cells (Figure 1D, lanes 2–6). The inter- ciation of the Cry:Tim complex. action of Tim with Jet is increased in the presence of Cry, sup- porting the idea that Cry:Tim or Jet:Cry complexes promote Jetlag Promotes Cryptochrome Degradation in Flies binding of Tim to Jet (Figure 1D, compare lanes 4 and 6). If the Jet:Cry interaction is biologically relevant, we would Why could we (and others) detect Tim:Jet interactions in expect to see an effect on Cry degradation in flies with reduced S2 cells [2], but not in yeast (Figure 1A)? The reason for this could jet function.
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