An Ancient Pseudoknot in TNF-α Pre-mRNA Activates PKR, Inducing eIF2α Phosphorylation that Potently Enhances Splicing

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Lise Sarah Namer, Farhat Osman, Yona Banai, Benoît Masquida, Rodrigo Jung, Raymond Kaempfer
Tumor necrosis factor alpha (TNF-α) is expressed promptly during inflammatory responses. Efficient TNF-α mRNA splicing is achieved through a 3′ UTR element that activates RNA-dependent eIF2α protein kinase (PKR). The TNF-α RNA activator, we show, folds into a pseudoknot conserved from teleost fish to humans, critical for PKR activation and mRNA splicing. The pseudoknot constrains the RNA into two double-helical stacks having parallel axes, permitting facile PKR dimerization and trans-autophosphorylation needed for kinase activation. Mutations show that the PKR activator potently enhances splicing without inhibiting translation. eIF2α phosphorylation represses translation and is essential for coping with cellular stress, yet PKR-enabled TNF mRNA splicing depends strictly on eIF2α phosphorylation. Indeed, eIF2α phosphorylation at Serine51 is necessary and sufficient to achieve highly efficient splicing, extending its role from negative control of translation to positive control of splicing. This mechanism, operational in human peripheral blood mononuclear cells (PBMCs), links stress signaling to protective immunity through TNF mRNA splicing rendered efficient upon eIF2α phosphorylation.

Graphical abstract

Teaser

Tumor necrosis factor (TNF) is expressed promptly during inflammatory responses. Namer et al. define the structure and function of a TNF RNA element that promotes mRNA splicing. It enables splicing by inducing phosphorylation of eIF2α by the RNA-activated enzyme PKR, a cellular stress response previously thought only to block translation.


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