The E3 ubiquitin ligase Slimb/β-TrCP is required for normal copper homeostasis in Drosophila

Zhang, Bichao; Binks, Tim; Burke, Richard

doi:10.1016/j.bbamcr.2020.118768

Cited by 12 publications

(6 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here, we measured the metallomes of the flies selected for light or dark pigment in the latter study, as well as mutant alleles for the y and e genes after these were crossed in two distinct genetic backgrounds, respectively. Our finding that total body copper correlates with melanin deposition is consistent with the previously shown biochemical link between this metal and cuticle pigmentation (Binks et al 2010 ; Turski and Thiele 2007 ; Zhang et al 2020 ; Zhou et al 2003 ).…”

Section: Introductionsupporting

confidence: 92%

“…Unfortunately, all flies used in this study were disposed of during the Covid-19 contingency and we cannot, regretfully, revisit this issue on the same set of flies. With these considerations in mind, and given the known requirement of copper for pigmentation (Binks et al 2010 ; Turski and Thiele 2007 ; Zhang et al 2020 ; Zhou et al 2003 ), in addition to other physiological processes (Comstra et al 2017 ; Kirby et al 2008 ; Sellami et al 2012 ; Theotoki et al 2019 ; Wang et al 2018 ), we conclude this report suggesting that the observed correlation between copper content and pigmentation in D. melanogaster could be explained by an increased requirement for tyrosinase activity for melanin production in this species. To further test this hypothesis, an unambiguous identification of the copper-dependent enzyme involved in epidermal pigment melanization would be helpful (Riedel et al 2010 ).…”

Section: Discussionmentioning

confidence: 99%

“…It should be noted, however, that the tyrosinase complex acting at the epithelial cells appears to be distinct from the prophenol oxidases that produce melanin during the immune response, given that deletion of all three prophenol oxidases rendered flies susceptible to microbial infection without altering their cuticle pigmentation (Binggeli et al 2014;Dudzic et al 2015). Yet, one of the enzymatic components was found to be a cuproenzyme (Seybold et al 1975;Sugumaran et al 1992) and, most importantly, the cuticle pigmentation activity required the presence of copper in vivo (Binks et al 2010;Turski and Thiele 2007;Zhang et al 2020;Zhou et al 2003).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cuticle darkening correlates with increased body copper content in Drosophila melanogaster

2020

View full text Add to dashboard Cite

Insect epidermal cells secrete a cuticle that serves as an exoskeleton providing mechanical rigidity to each individual, but also insulation, camouflage or communication within their environment. Cuticle deposition and hardening (sclerotization) and pigment synthesis are parallel processes requiring tyrosinase activity, which depends on an unidentified copperdependent enzyme component in Drosophila melanogaster. We determined the metallomes of fly strains selected for lighter or darker cuticles in a laboratory evolution experiment, asking whether any specific element changed in abundance in concert with pigment deposition. The results showed a correlation between total iron content and strength of pigmentation, which was further corroborated by ferritin iron quantification. To ask if the observed increase in iron body content along with increased pigment deposition could be generalizable, we crossed yellow and ebony alleles causing light and dark pigmentation, respectively, into similar genetic backgrounds and measured their metallomes. Iron remained unaffected in the various mutants providing no support for a causative link between pigmentation and iron content. In contrast, the combined analysis of both experiments suggested instead a correlation between pigment deposition and total copper body content, possibly due to increased demand for epidermal tyrosinase activity. Keywords Color Á Elemental analysis Á Genetic background Á Melanin Á Zinc

show abstract

Section: Introductionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cuticle darkening correlates with increased body copper content in Drosophila melanogaster

2020

View full text Add to dashboard Cite

show abstract

“…Mosquitoes were fed on P. berghei infected blood on day five of adulthood as in the previous experiments. These metal chelators have been used before in D. melanogaster at dietary concentrations between 100 and 300 μM, acting with proven metal specificities [74,75]. As previously shown for some Anopheles species [76][77][78], P. berghei infection affected follicular development in 51% (n = 47) of the susceptible ws female mosquitoes and 22% (n = 41) of the resistant bs counterparts (Fig 4).…”

Section: The Effects Of Iron and Copper Chelation On The Outcome Of P Berghei Infections And Follicular Developmentmentioning

confidence: 63%

Mosquito metallomics reveal copper and iron as critical factors for Plasmodium infection

et al. 2021

View full text Add to dashboard Cite

Iron and copper chelation restricts Plasmodium growth in vitro and in mammalian hosts. The parasite alters metal homeostasis in red blood cells to its favor, for example metabolizing hemoglobin to hemozoin. Metal interactions with the mosquito have not, however, been studied. Here, we describe the metallomes of Anopheles albimanus and Aedes aegypti throughout their life cycle and following a blood meal. Consistent with previous reports, we found evidence of maternal iron deposition in embryos of Ae. aegypti, but less so in An. albimanus. Sodium, potassium, iron, and copper are present at higher concentrations during larval developmental stages. Two An. albimanus phenotypes that differ in their susceptibility to Plasmodium berghei infection were studied. The susceptible white stripe (ws) phenotype was named after a dorsal white stripe apparent during larval stages 3, 4, and pupae. During larval stage 3, ws larvae accumulate more iron and copper than the resistant brown stripe (bs) phenotype counterparts. A similar increase in copper and iron accumulation was also observed in the susceptible ws, but not in the resistant bs phenotype following P. berghei infection. Feeding ws mosquitoes with extracellular iron and copper chelators before and after receiving Plasmodium-infected blood protected from infection and simultaneously affected follicular development in the case of iron chelation. Unexpectedly, the application of the iron chelator to the bs strain reverted resistance to infection. Besides a drop in iron, iron-chelated bs mosquitoes experienced a concomitant loss of copper. Thus, the effect of metal chelation on P. berghei infectivity was strain-specific.

show abstract

“…This tunable switch markedly promotes target polyubiquitination and can thus regulate the degradation rate of many proteins, contributing to development and, notably, head formation in Drosophila . While we demonstrated that E2D2 activation is a major component of the copper-induced polyubiquitination blush, and that activation of the E2D clade is likely to mediate much of the protein turnover induced by copper supplementation in cell culture, we have not excluded lesser contributions from other components of the ubiquitin-proteasomal system, including potential interplay between copper and E3 ligases( 55 ) or deubiquitinating enzymes( 56 ).…”

Section: Discussionmentioning

confidence: 77%

Nutrient copper signaling promotes protein turnover by allosteric activation of ubiquitin E2D conjugases

Lotan

Xiao

et al. 2021

Preprint

View full text Add to dashboard Cite

Fine-tunning of ubiquitin-conjugating enzymes (E2s), which orchestrate posttranslational modifications that control protein and cell fate, remains largely elusive. Recently, copper signaling emerged as a critical regulator of cell growth and neuronal differentiation, yet confluence of these key pathways has not been reported. Here we show that subtle rises in cellular copper strikingly increase polyubiquitination in numerous mammalian cell lines, while markedly accelerating protein degradation. Using biochemistry, proteomics, NMR spectroscopy and mutational analyses, we link Cu+-enhanced protein ubiquitination and degradation to an evolutionarily conserved CXXXC motif in the E2D (UBE2D) clade. Cu+ binding to this sub-femtomolar-affinity site induces allosteric changes that transduce to the active site region and increase enzyme activity. This machinery couples physiologic fluctuations in cytoplasmic Cu+ with the degradation rate of numerous proteins including the canonical substrate, p53. In Drosophila harboring a larval-lethal UbcD1 knockdown, human E2D2 expression supported near-normal development but ablation of its Cu+ binding site profoundly disrupted head development. Our findings introduce Cu+ as a novel regulator of E2D activity through an allosteric switch whose emergence coincided with animal multicellularity. Through this unexpected signaling mechanism, crosstalk between copper and protein ubiquitination could have broad impact including upon neurobiological development and cell cycling.

show abstract

The E3 ubiquitin ligase Slimb/β-TrCP is required for normal copper homeostasis in Drosophila

Cited by 12 publications

References 55 publications

Cuticle darkening correlates with increased body copper content in Drosophila melanogaster

Cuticle darkening correlates with increased body copper content in Drosophila melanogaster

Mosquito metallomics reveal copper and iron as critical factors for Plasmodium infection

Nutrient copper signaling promotes protein turnover by allosteric activation of ubiquitin E2D conjugases

Contact Info

Product

Resources

About