Eukaryotic elongation factor 2 controls TNF-α 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-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 elongation is poorly understood. We found that expression of p38γ/δ MAPK proteins is required for the elongation of nascent TNF-α protein in macrophages. The MKK3/6-p38γ/δ pathway mediated an inhibitory phosphorylation of eukaryotic elongation factor 2 (eEF2) kinase, which in turn promoted eEF2 activation (dephosphorylation) and subsequent TNF-α elongation. These results identify a new signaling pathway that regulates TNF-α production in LPS-induced liver damage and suggest potential cell-specific therapeutic targets for liver diseases in which TNF-α production is involved.

TNF and MAP kinase signalling pathways

“…Key regulators of Tnfα mRNA expression include NF-κB and members of the mitogen-activated protein kinase (MAPK) family. Moreover, MAP kinases play central roles in TNFα post-transcriptional regulation, including nuclear export of Tnfα mRNA, Tnfα mRNA stabilization through cis -elements in the 3′ untranslated-region (3′-UTR), Tnfα mRNA translation, and shedding of soluble TNFα [63, 64]. …”

“…The p38γ MAP kinase is expressed in all tissues and is expressed at high levels in muscle [90]. The p38δ MAP kinase is highly expressed in a limited number of tissues, including neutrophils and endocrine glands [20, 64, 91, 92]. The p38 MAPK family can be sub-divided into two subsets on the basis of sequence homology, substrate specificity, and sensitivity to chemical inhibitors [94]: 1) p38α and p38β MAP kinases; and 2) p38γ and p38δ MAP kinases.…”

“…This role of p38α MAP kinase is mediated by regulation of Tnfα mRNA stability and translation initiation. More recently, the p38γ and p38δ MAP kinase isoforms were found to play an important role in TNFα production by regulating Tnfα mRNA translation elongation [64]. …”

“…Recent studies have demonstrated that the p38γ and p38δ MAP kinase isoforms also play key roles in post-transcriptional regulation of TNFα biosynthesis [64, 126]. Studies using mice with myeloid-specific p38γ/δ gene ablation identified defects in translational elongation of nascent pro-TNFα protein [64].…”

“…Studies using mice with myeloid-specific p38γ/δ gene ablation identified defects in translational elongation of nascent pro-TNFα protein [64]. This defect in translation elongation was mediated by eukaryotic elongation factor 2 (eEF2) kinase [64], a protein kinase that promotes translational elongation and is regulation by inhibitory phosphorylation by the p38γ/δ MAP kinases [24].…”