NEDD8 conjugation in Schistosoma mansoni: Genome analysis and expression profiles

Abstract

NEDD8 is an ubiquitin-like molecule that covalently binds to target proteins through an enzymatic cascade analogous to ubiquitylation. This modifier is known to bind to p53 and p73, as well as all Cullin family proteins, which are essential components of Skp1/Cul-1/F-box protein (SCF)-like Ub ligase complexes. Here, we focused on a genomic analysis of the genes involved in the NEDD8 conjugation pathway in Schistosoma mansoni. The results revealed seven genes related to NEDD8 conjugation that are conserved in Schistosoma japonicum, Caenorhabditis elegans, Drosophila melanogaster and Homo sapiens. We performed quantitative RT-PCR (qRT-PCR), which showed differential profiles for Smnedd8, Smapp1, Smuba3, Smube2f, Smdcn1, Smrbx and Smsenp8 throughout the life cycle of S. mansoni. Upregulation was observed in 3-day-old schistosomula and adult worms for all analysed genes. We also analysed the transcription levels of Cullin family members Smp63 and Smp73, and observed upregulation in early schistosomula, while cercariae and adult worms showed expression levels similar to one another. Taken together, these results suggest that the NEDDylation/DeNEDDylation pathway controls important cellular regulators during worm development from cercariae to schistosomula and, finally, to adult.

Inhibiting Neddylation with MLN4924 Suppresses Growth and Delays Multicellular Development in Dictyostelium discoideum

“…In this study, we showed that neddylation is required for the growth and multicellular development of D. discoideum, which complements similar work in other organisms (e.g., parasitic protozoa, fungi, plants, animals, and humans) to better understand the biological roles of neddylation (Figure 8) [23][24][25][26][27]. The expression and amount of free Nedd8 peaked during the early stages of multicellular development, and then decreased dramatically during the mid-to-late stages.…”

“…In addition, the complete loss of neddylation is lethal in many eukaryotic organisms [4,21,22]. Although neddylation has been well-studied in a variety of organisms including parasitic protozoa, fungi, plants, animals, and humans, the pathway has not yet been explored in detail in amoebozoa such as Dictyostelium discoideum [23][24][25][26][27]. D. discoideum is a unikont that emerged at least 600 million years ago, prior to the fungi-animal split [28].…”

Ubiquitin-specific proteases are differentially expressed throughout the Schistosoma mansoni life cycle

“…These combined effects determine functional p53 levels, creating an important role for USP7 in p53-dependent stress responses. Our group showed that the p53 orthologues, p63 and p73 [ 50 ], are up-regulated in MTS-3.5 h and MTS-5 days [ 51 ]. We also observed a differential expression profile for Smusp7.…”

Discovery of Potent and Selective 2-(Benzylthio)pyrimidine-based DCN1-UBC12 Inhibitors for Anticardiac Fibrotic Effects

“…Cullin–RING ligases (CRLs), the central ingredient of the ubiquitin–proteasome system, are regulated by several pathways in which neddylation modification is the crucial process for cullin activation. − Analogous to the ubiquitin pathway, the neddylation pathway contains a set of enzymes working together to conjugate NEDD8 to specific target proteins and thus regulate their functions . The tripartite enzymatic cascade of neddylation comprises NEDD8-activating enzyme E1s (NAE1, UBA3), two NEDD8-conjugating enzymes E2s (UBE2F, UBC12), and NEDD8-E3 ligases, , with cullins being the best-characterized substrates (Figure A) .…”