Activation of the elongation factor 2 kinase (eEF2K) leads to the phosphorylation and inhibition of the elongation factor eEF2, reducing mRNA translation rates. Emerging evidence indicates that the regulation of factors involved in protein synthesis may be critical for controlling diverse biological processes including cancer progression. Here we show that inhibitors of the HIV aspartyl protease (HIV-PIs), nelfinavir in particular, trigger a robust activation of eEF2K leading to the phosphorylation of eEF2. Beyond its anti-viral effects, nelfinavir has antitumoral activity and promotes cell death. We show that nelfinavir-resistant cells specifically evade eEF2 inhibition. Decreased cell viability induced by nelfinavir is impaired in cells lacking eEF2K. Moreover, nelfinavir-mediated anti-tumoral activity is severely compromised in eEF2K-deficient engrafted tumors in vivo. Our findings imply that exacerbated activation of eEF2K is detrimental for tumor survival and describe a mechanism explaining the anti-tumoral properties of HIV-PIs.
SignificanceCD4 T cells are major regulators of immune responses against both self and pathogens. Understanding pathways that govern CD4 T cell differentiation and regulation are thus key for the discovery of new immunoregulatory drug targets. Here, we have identified an epigenetic pathway that regulates the expression of a set of proteins that determine T cell responsiveness. By silencing enhancers distal to a set of genes known to be involved in regulatory T cell function, the epigenetic modifiers TRIM28 and HP1β/γ regulate T cell receptor signaling. This leads to defective metabolic reprograming and inefficient effector differentiation of naive T cells. This mechanism provides an exciting opportunity to regulate T cell responsivity in both autoimmunity and T cell-based immunodeficiencies.
Author contributions: D.P. performed all experiments and analyzed data. G.P. made substantial technical contributions to acquisition of in vitro T cell assay data (Fig.
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