The eukaryotic translation initiation regulator CDC123 defines a divergent clade of ATP-grasp enzymes with a predicted role in novel protein modifications

Abstract

Deciphering the origin of uniquely eukaryotic features of sub-cellular systems, such as the translation apparatus, is critical in reconstructing eukaryogenesis. One such feature is the highly conserved, but poorly understood, eukaryotic protein CDC123, which regulates the abundance of the eukaryotic translation initiation eIF2 complex and binds one of its components eIF2γ. We show that the eukaryotic protein CDC123 defines a novel clade of ATP-grasp enzymes distinguished from all other members of the superfamily by a RAGNYA domain with two conserved lysines (henceforth the R2K clade). Combining the available biochemical and genetic data on CDC123 with the inferred enzymatic function, we propose that the eukaryotic CDC123 proteins are likely to function as ATP-dependent protein-peptide ligases which modify proteins by ribosome-independent addition of an oligopeptide tag. We also show that the CDC123 family emerged first in bacteria where it appears to have diversified along with the two other families of the R2K clade. The bacterial CDC123 family members are of two distinct types, one found as part of type VI secretion systems which deliver polymorphic toxins and the other functioning as potential effectors delivered to amoeboid eukaryotic hosts. Representatives of the latter type have also been independently transferred to phylogenetically unrelated amoeboid eukaryotes and their nucleo-cytoplasmic large DNA viruses. Similarly, the two other prokaryotic R2K clade families are also proposed to participate in biological conflicts between bacteriophages and their hosts. These findings add further evidence to the recently proposed hypothesis that the horizontal transfer of enzymatic effectors from the bacterial endosymbionts of the stem eukaryotes played a fundamental role in the emergence of the characteristically eukaryotic regulatory systems and sub-cellular structures.ReviewersThis article was reviewed by Michael Galperin and Sandor Pongor.Electronic supplementary materialThe online version of this article (doi:10.1186/s13062-015-0053-x) contains supplementary material, which is available to authorized users.

Genetics and Genomic Regions Affecting Response to Newcastle Disease Virus Infection under Heat Stress in Layer Chickens

“…Of particular interest are three immune-related genes ( CDC123 , CAMK1d, and CCDC3 ) located within the 1 Mb QTL region identified on chromosome 1 centered around the suggestive SNP associated with the viral titer 2 dpi. CDC123 is a gene that is highly expressed in leukocytes and plays a role in eIF2 regulation and internal host-pathogen interaction [39]. Unpublished data from our group also found CDC123 to be significantly up-regulated in NDV infected and heat stressed Fayoumi chickens compared to non-treated birds.…”

“…Other immune response genes in this QTL region, such as TIRAP , FLI1 , and ST3GAL4 , could be critical in terms of the broader response to the virus at 6 dpi. TIRAP is a Toll-interleukin 1 receptor adaptor protein that is part of the microbial pathogen recognition system of Toll-like receptors and functions in pathogen recognition within the host [39]. TIRAP codes for proteins that activate TLR4 signaling and initiates genes such as NF-κB , MAPK1 , MAPK3 , and JNK for cytokine secretion and inflammatory response.…”

Genetic Analyses of Tanzanian Local Chicken Ecotypes Challenged with Newcastle Disease Virus

“…TIRAP had three significant SNPs downstream of it that were associated with viral load at 6 dpi (Table 5). TIRAP is a Toll-interleukin 1 receptor [45] that recognizes pathogens within a host and is part of the microbial pathogen recognition Toll-like receptor system [46]. TIRAP is an adaptor protein that activates TLR4 signaling and is involved in modulating early innate immune response through detection of viral envelope glycoprotein [47].…”

Genes associated with polymorphic variants predicting lung function are differentially expressed during human lung development

“…Of the most robust findings; i.e., where mRNA differential expression was supported by differential protein expression in the same direction; CDC123 expression (decreased) and TMEM163 (increased) warrant further study. CDC123 is thought to be required for translation initiation and thus could facilitate the biogenesis of the eukaryotic initiation factor 2 (eIF2) and is also potentially involved in protein modifications [ 22 , 23 ]. At present, there is evidence that TMEM163 (SV13) is a zinc finger binding protein involved in vesicular transport [ 24 ] and more recent work has shown TMEM163’s modulation of cellular zinc levels alongside TRPML1 [ 25 ].…”