Unique posttranslational modifications in eukaryotic translation factors and their roles in protozoan parasite viability and pathogenesis

Mittal, Nimisha; Subramanian, Gowri; Bütikofer, Peter; Madhubala, Rentala

doi:10.1016/j.molbiopara.2012.11.001

Cited by 17 publications

(12 citation statements)

References 76 publications

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“…The same applies to other irreversible post-translational modifications and in general to all cases where the detected peptide or protein is lost from the pool of analyzed species as it is the case, for example, for secreted proteins. Accordingly, it is conceivable that the high turnover rate of the peptide encompassing His715 in EEF2 might also reflect the rate of diphthamide modification (51). Similarly, the turnover of peptides comprising cleavage sites in CTSD and PSAP, might as well illustrate the proteolytic process itself.…”

Section: Discussionmentioning

confidence: 99%

Peptide Level Turnover Measurements Enable the Study of Proteoform Dynamics

Zecha

Meng

Zolg

et al. 2018

Molecular & Cellular Proteomics

109

162

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Section: Discussionmentioning

confidence: 99%

Peptide Level Turnover Measurements Enable the Study of Proteoform Dynamics

Zecha

Meng

Zolg

et al. 2018

Molecular & Cellular Proteomics

109

162

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“…However, the extent of changes in translational factors observed in SEC63 silenced cells is of special interest, since changes in the level of these factors (elongation factor 1b, translation initiation factor 2g, elongation factor 1a and initiation factor 5A) and the modifications that these undergo may lead to the shut-off of protein synthesis. Indeed, the same translation factors were shown to undergo parasite-unique modifications, suggesting that these factors may be more critical than others in controlling translation (Mittal et al, 2012). The modification and changes in the level of TEF1-a is of special interest because this abundant protein, which comprises 3-10% of the proteins in the cell, may have additional functions beyond translation control, such as association with the proteasome and cytoskeleton.…”

Section: Transcriptome and Proteome Changes Affecting Protein Synthesmentioning

confidence: 99%

Transcriptome and proteome analyses and the role of atypical calpain protein and autophagy in the spliced leader silencing pathway in Trypanosoma brucei

Hope

Egarmina

Voloshin

et al. 2016

Molecular Microbiology

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Under persistent ER stress, Trypanosoma brucei parasites induce the spliced leader silencing (SLS) pathway. In SLS, transcription of the SL RNA gene, the SL donor to all mRNAs, is extinguished, arresting trans-splicing and leading to programmed cell death (PCD). In this study, we investigated the transcriptome following silencing of SEC63, a factor essential for protein translocation across the ER membrane, and whose silencing induces SLS. The proteome of SEC63-silenced cells was analyzed with an emphasis on SLS-specific alterations in protein expression, and modifications that do not directly result from perturbations in trans-splicing. One such protein identified is an atypical calpain SKCRP7.1/7.2. Co-silencing of SKCRP7.1/7.2 and SEC63 eliminated SLS induction due its role in translocating the PK3 kinase. This kinase initiates SLS by migrating to the nucleus and phosphorylating TRF4 leading to shut-off of SL RNA transcription. Thus, SKCRP7.1 is involved in SLS signaling and the accompanying PCD. The role of autophagy in SLS was also investigated; eliminating autophagy through VPS34 or ATG7 silencing demonstrated that autophagy is not essential for SLS induction, but is associated with PCD. Thus, this study identified factors that are used by the parasite to cope with ER stress and to induce SLS and PCD.

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“…This demonstrates that the attachment of glutamine is strictly specific for Glu 45 . Besides glutaminylation of eEF1A, there are three other "unusual" posttranslational modifications also found in eukaryotic ribosome-associated factors (28): EPG modification of Glu 301 and Glu 374 in eEF1A, hypusine modification of eukaryotic initiation factor 5A (eIF5A), and diphthamide modification of eukaryotic elongation factor 2 (eEF2) (29). The precise functional roles of these modifications are not well-understood.…”

Section: Discussionmentioning

confidence: 99%

Protein glutaminylation is a yeast-specific posttranslational modification of elongation factor 1A

Jank

Belyi²,

Wirth

et al. 2017

Journal of Biological Chemistry

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Ribosomal translation factors are fundamental for protein synthesis and highly conserved in all kingdoms of life. The essential eukaryotic elongation factor 1A (eEF1A) delivers aminoacyl tRNAs to the A-site of the translating 80S ribosome. Several studies have revealed that eEF1A is posttranslationally modified. Using MS analysis, site-directed mutagenesis, and X-ray structural data analysis of Saccharomyces cerevisiae eEF1A, we identified a posttranslational modification in which the ␣ amino group of mono-L-glutamine is covalently linked to the side chain of glutamate 45 in eEF1A. The MS analysis suggested that all eEF1A molecules are modified by this glutaminylation and that this posttranslational modification occurs at all stages of yeast growth. The mutational studies revealed that this glutaminylation is not essential for the normal functions of eEF1A in S. cerevisiae. However, eEF1A glutaminylation slightly reduced growth under antibiotic-induced translational stress conditions. Moreover, we identified the same posttranslational modification in eEF1A from Schizosaccharomyces pombe but not in various other eukaryotic organisms tested despite strict conservation of the Glu 45 residue among these organisms. We therefore conclude that eEF1A glutaminylation is a yeast-specific posttranslational modification that appears to influence protein translation.One of the most conserved biological processes is ribosomal protein synthesis, comprising initiation, elongation, termination, and recycling steps. Each step is dependent on specific translation factors. Eukaryotic elongation factor 1A (eEF1A), 4 a large GTPase that is one of the most abundant cytosolic proteins, is important for the binding, stabilization, and delivery of aminoacylated tRNA to the translating ribosome. Correct codon-anticodon pairing of the aminoacyl-tRNA with the mRNA at the ribosomal A-site triggers ribosome-dependent hydrolysis of GTP and leads to dissociation of eEF1A from the ribosome. eEF1A is reactivated by nucleotide exchange factor eEF1B (1) and then able to reassociate with charged tRNA to start a new translation cycle. Besides its essential role in mRNA translation, eEF1A participates in many other cellular functions and is reportedly involved in actin bundling, nuclear export (2), signal transduction (3), apoptosis, proteasomal degradation, and tumorigenesis (4, 5).Crystal structures of archaeal, mammalian, and yeast eEF1A (partially in complex with subunits of eEF1B) showed that the elongation factor consists of three domains (I-III) (6 -8). Domain I is the GTP-binding domain and resembles GTPases of the Ras family. Domains II and III are likely to act as a rigid functional unit and are involved in aminoacyl-tRNA binding. These domains were also reported to be implicated in the interaction with cytoskeletal proteins (9, 10).eEF1A is extensively posttranslationally modified by lysyl acetylation, methylation (11), ubiquitination, nitrosylation, glutathionylation, phosphorylation (12), C-terminal methyl esterification (13), and the att...

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Unique posttranslational modifications in eukaryotic translation factors and their roles in protozoan parasite viability and pathogenesis

Cited by 17 publications

References 76 publications

Peptide Level Turnover Measurements Enable the Study of Proteoform Dynamics

Peptide Level Turnover Measurements Enable the Study of Proteoform Dynamics

Transcriptome and proteome analyses and the role of atypical calpain protein and autophagy in the spliced leader silencing pathway in Trypanosoma brucei

Protein glutaminylation is a yeast-specific posttranslational modification of elongation factor 1A

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