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Eukaryotic elongation factor 2 controls TNF-? translation in LPS-induced hepatitis.

ABSTRACT: Bacterial LPS (endotoxin) has been implicated in the pathogenesis of acute liver disease through its induction of the proinflammatory cytokine TNF-?. TNF-? is a key determinant of the outcome in a well-established mouse model of acute liver failure during septic shock. One possible mechanism for regulating TNF-? expression is through the control of protein elongation during translation, which would allow rapid cell adaptation to physiological changes. However, the regulation of translational elongation is poorly understood. We found that expression of p38?/? MAPK proteins is required for the elongation of nascent TNF-? protein in macrophages. The MKK3/6-p38?/? pathway mediated an inhibitory phosphorylation of eukaryotic elongation factor 2 (eEF2) kinase, which in turn promoted eEF2 activation (dephosphorylation) and subsequent TNF-? elongation. These results identify a new signaling pathway that regulates TNF-? production in LPS-induced liver damage and suggest potential cell-specific therapeutic targets for liver diseases in which TNF-? production is involved.

SUBMITTER: Gonzalez-Teran B

PROVIDER: S-EPMC3533299 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Eukaryotic elongation factor 2 controls TNF-α translation in LPS-induced hepatitis.

González-Terán Bárbara B Cortés José R JR Manieri Elisa E Matesanz Nuria N Verdugo Ángeles Á Rodríguez María E ME González-Rodríguez Águeda Á González-Rodríguez Águeda Á Valverde Ángela M ÁM Martín Pilar P Davis Roger J RJ Sabio Guadalupe G

The Journal of clinical investigation 20121203 1

Bacterial LPS (endotoxin) has been implicated in the pathogenesis of acute liver disease through its induction of the proinflammatory cytokine TNF-α. TNF-α is a key determinant of the outcome in a well-established mouse model of acute liver failure during septic shock. One possible mechanism for regulating TNF-α expression is through the control of protein elongation during translation, which would allow rapid cell adaptation to physiological changes. However, the regulation of translational elo ...[more]

PMID: 23202732

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Project description:BackgroundRegulation of gene expression in trypanosomatids is mainly posttranscriptional. Tight regulation of mRNA stability and access to polysomes allows Trypanosoma cruzi to adapt to different environmental conditions during its life cycle. Posttranscriptional regulation requires association between mRNAs and specific proteins to form mRNP complexes. Proteins that lack a canonical RNA-binding domain, such as eukaryotic elongation factor-1α (EF-1α), may also associate with mRNPs. EF-1α is conserved in many organisms, and it plays roles in many cellular processes other than translation, including RNA transport, the cell cycle, and apoptosis.ResultsIn a previous study, EF-1α was found associated with mRNP-forming mRNAs in polysome-free fractions both in epimastigotes growing under normal conditions and in nutritionally stressed parasites. This finding suggested the possibility that EF-1α has a non-canonical function. Thus, we investigated the dynamics of EF-1α in association with T. cruzi epimastigote mRNAs under normal and stressed nutritional conditions. EF-1α is expressed throughout the parasite life cycle, but it shows a slight decrease in protein levels in the metacyclic trypomastigote form. The protein is cytoplasmically localized with a granular pattern in all forms analyzed. Following puromycin treatment, EF-1α migrated with the heaviest gradient fractions in a sucrose polysome profile, indicating that its association with large protein complexes was independent of the translation machinery. We next characterized the EF-1α-associated mRNAs in unstressed and stressed epimastigotes. We observed that specific subsets of mRNAs were associated with EF-1α-mRNPs in unstressed or stressed epimastigotes. Some mRNAs were identified in both physiological conditions, whereas others were condition-specific. Gene ontology analysis identified enrichment of gene sets involved in single-organism metabolic processes, amino acid metabolic processes, ATP and metal ion binding, glycolysis, glutamine metabolic processes, and cobalt and iron ion binding.ConclusionThese results indicate that in T. cruzi, as in other eukaryotes, EF-1α may play a non-canonical cellular role. We observed the enrichment of functionally related transcripts bound to EF-1α in normal growth conditions as well as in nutritionally stressed cell indicating a potential role of EF-1α mRNP in stress response.

Dataset Information

Eukaryotic elongation factor 2 controls TNF-? translation in LPS-induced hepatitis.

Publications

Eukaryotic elongation factor 2 controls TNF-α translation in LPS-induced hepatitis.

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