High levels of eukaryotic Initiation Factor 6 (eIF6) are required for immune system homeostasis and for steering the glycolytic flux of TCR-stimulated CD4+ T cells in both mice and humans

Abstract

Eukaryotic Initiation Factor 6 (eIF6) is required for 60S ribosomal subunit biogenesis and efficient initiation of translation. Intriguingly, in both mice and humans, endogenous levels of eIF6 are detrimental as they act as tumor and obesity facilitators, raising the question on the evolutionary pressure that maintains high eIF6 levels. Here we show that, in mice and humans, high levels of eIF6 are required for proper immune functions. First, eIF6 heterozygous (het) mice show an increased mortality during viral infection and a reduction of peripheral blood CD4 Effector Memory T cells. In human CD4 T cells, eIF6 levels rapidly increase upon T-cell receptor activation and drive the glycolytic switch and the acquisition of effector functions. Importantly, in CD4 T cells, eIF6 levels control interferon-γ (IFN-γ) secretion without affecting proliferation. In conclusion, the immune system has a high evolutionary pressure for the maintenance of a dynamic and powerful regulation of the translational machinery.

Data on the effects of eIF6 downmodulation on the proportions of innate and adaptive immune system cell subpopulations and on thymocyte maturation

“…Value of the data Albeit preserving precise levels of eIF6 is of physiological importance [1] , [2] , [3] , [4] , [5] , [6] , our data indicate that eIF6 depletion does not alter the proportions of specific innate and adaptive immune system cell subpopulations nor the capability of the thymus to correctly produce mature thymocytes. These data could be a useful starting point for further characterization of the role of eIF6 and of translation in general in immune system regulation.…”

“… The data described in this article are related to “High levels of eukaryotic Initiation Factor 6 (eIF6) are required for immune system homeostasis and for steering the glycolytic flux of TCR-stimulated CD4 + T cells in both mice and humans” (Manfrini et al, in press) [1] . eIF6 is a translation initiation factor required for ribosomal biogenesis (Sanvito et al, 1999) [2] and for proper translational initiation (Gallo and Manfrini, 2015; Miluzio et al, 2016) [3] , [4] whose protein abundance requires tight regulation.…”

Discovery and Preliminary Characterization of Translational Modulators that Impair the Binding of eIF6 to 60S Ribosomal Subunits

“…Eukaryotic initiation factor 6 is a powerful ribosome-associated factor that performs two functions: it acts as an essential trans-actor factor in the generation and quality control of 60S subunits [15,51] and as a translation factor in the cytoplasm. eIF6 is essential for efficient growth factor-stimulated translation [16,17,[24][25][26][52][53][54]. It is assumed that the biological activity of eIF6 resides in its capability to bind in a regulated fashion 60S ribosomal subunits, as it was shown originally by biochemical studies [14] and later confirmed by structural work [55].…”

Genomic analysis of a cypovirus isolated from the eucalyptus brown looper, Thyrinteina arnobia (Stoll, 1782) (Lepidoptera: Geometridae)

“…The segment 8 sequence is only present in Cypovirus 14 isolates and seemed to be an autapomorphy for this species complex. We found a domain in the S8 segment related to the eukaryotic initiation factor 6 (eIF6), associated with protein translation (Manfrini et al, 2017). The impact and the function of each segment is not clear for most of the described CPVs so far.…”