Decoding the Ubiquitin-Mediated Pathway of Arthropod Disease Vectors

Abstract

Protein regulation by ubiquitin has been extensively described in model organisms. However, characterization of the ubiquitin machinery in disease vectors remains mostly unknown. This fundamental gap in knowledge presents a concern because new therapeutics are needed to control vector-borne diseases, and targeting the ubiquitin machinery as a means for disease intervention has been already adopted in the clinic. In this study, we employed a bioinformatics approach to uncover the ubiquitin-mediated pathway in the genomes of Anopheles gambiae, Aedes aegypti, Culex quinquefasciatus, Ixodes scapularis, Pediculus humanus and Rhodnius prolixus. We observed that (1) disease vectors encode a lower percentage of ubiquitin-related genes when compared to Drosophila melanogaster, Mus musculus and Homo sapiens but not Saccharomyces cerevisiae; (2) overall, there are more proteins categorized as E3 ubiquitin ligases when compared to E2-conjugating or E1-activating enzymes; (3) the ubiquitin machinery within the three mosquito genomes is highly similar; (4) ubiquitin genes are more than doubled in the Chagas disease vector (R. prolixus) when compared to other arthropod vectors; (5) the deer tick I. scapularis and the body louse (P. humanus) genomes carry low numbers of E1-activating enzymes and HECT-type E3 ubiquitin ligases; (6) R. prolixus have low numbers of RING-type E3 ubiquitin ligases; and (7) C. quinquefasciatus present elevated numbers of predicted F-box E3 ubiquitin ligases, JAB and UCH deubiquitinases. Taken together, these findings provide novel opportunities to study the interaction between a pathogen and an arthropod vector.

An Rtf2 Domain-Containing Protein Influences Pre-mRNA Splicing and Is Essential for Embryonic Development in Arabidopsis thaliana

“…Another example noted in the study of Korneta et al (2012) is NOSIP (nitric oxide synthase interacting protein) (CG6179), which contains an Rtf2 domain and is a component of the Drosophila melanogaster spliceosome (Herold et al 2009). The Rtf2 domain has been annotated in association with RING E3 ubiquitin ligases (Choy et al 2013) and suggested to act as an ubiquitin ligase in the context of splicing (Korneta et al 2012). A divergent cyclophilin that may be involved in splicing also contains an Rtf2 domain (Page and Winter 1998).…”

Evidence of an Antimicrobial Peptide Signature Encrypted in HECT E3 Ubiquitin Ligases

“…However, it is also possible that other classes of E3s can be involved in releasing additional HDPs. In fact, the results summarized in Table 2 show that other HECT-containing E3s also produce functional peptides, such as HECW1 and HECW2; therefore, it is likely that other E3s can mediate the production of functional peptides, consistent with the low numbers of HECT-containing ligases in arachnid genomes (63). Indeed, while Nedd4 or Nedd4-2-deficient mice show a variety of phenotypes including embryonic and neonatal lethality (60), recent studies provided evidence that other classes of E3s (RING-containing) play a role in arachnid host defense, at least against the bacterial pathogen Anaplasma phagocytophilum (64–66), as suggested by silencing the E3 ligase XIAP in I. scapularis ticks (64).…”

Ubiquitin Proteasome pathway proteins as potential drug targets in parasite Trypanosoma cruzi

“…In this case, due to no difference between thresholds, results from the e-value 0.1 cutoff was selected for further analysis. A total of 1,229 UPPs in H. sapiens have been analyzed previously with a cutoff of 0.5 e-value using HMM search 23 . While we report 1,227 UPP proteins in H. Sapiens (see Table 1 ), this is consistent with reported data sets.…”

“…Twenty-four Pfam motifs found in ubiquitin proteasome system were selected and downloaded from Pfam HMM library version 22.0 44 . The following Pfam domains were included Ufm1, PF03671; APG12, PF04110; Atg8, PF02991; ubiquitin, PF00240; Urm1, PF09138; ThiF, PF00899; UBACT, PF02134; UQ-con, PF00179; zf-C3HC4, PF00097; zf-RING-like, PF08746; zf-MIZ, PF02891; HECT, PF00632; Cullin, PF00888; U-box, PF04564; F-box, PF00646; OTU, PF02338; Josephin, PF02099; JAB, PF01398; DUF862, PF05903; WLM, PF08325; UCH, PF00443; Peptidase C12, PF01088; Peptidase C48, PF02902; and Peptidase C54, PF03416 23 , 24 .…”