Functionally distinct roles for eEF2K in the control of ribosome availability and p-body abundance

Patrick R. Smith, Sarah Loerch, Nikesh Kunder, Alexander D. Stanowick, Tzu-Fang Lou and Zachary T. Campbell ()
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Patrick R. Smith: The University of Texas at Dallas, Department of Biological Sciences
Sarah Loerch: Janelia Research Campus, Howard Hughes Medical Institute
Nikesh Kunder: The University of Texas at Dallas, Department of Biological Sciences
Alexander D. Stanowick: The University of Texas at Dallas, Department of Biological Sciences
Tzu-Fang Lou: The University of Texas at Dallas, Department of Biological Sciences
Zachary T. Campbell: The University of Texas at Dallas, Department of Biological Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Processing bodies (p-bodies) are a prototypical phase-separated RNA-containing granule. Their abundance is highly dynamic and has been linked to translation. Yet, the molecular mechanisms responsible for coordinate control of the two processes are unclear. Here, we uncover key roles for eEF2 kinase (eEF2K) in the control of ribosome availability and p-body abundance. eEF2K acts on a sole known substrate, eEF2, to inhibit translation. We find that the eEF2K agonist nelfinavir abolishes p-bodies in sensory neurons and impairs translation. To probe the latter, we used cryo-electron microscopy. Nelfinavir stabilizes vacant 80S ribosomes. They contain SERBP1 in place of mRNA and eEF2 in the acceptor site. Phosphorylated eEF2 associates with inactive ribosomes that resist splitting in vitro. Collectively, the data suggest that eEF2K defines a population of inactive ribosomes resistant to recycling and protected from degradation. Thus, eEF2K activity is central to both p-body abundance and ribosome availability in sensory neurons.

Date: 2021
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DOI: 10.1038/s41467-021-27160-4

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