Starvation is a common and challenging stressor for living organisms, compelling them to activate various biological responses to survive. Recent findings highlight the role of eukaryotic elongation factor 2 kinase (eEF2K), known as EFK-1 in the nematode Caenorhabditis elegans, as a key player not just through its conventional pathways but also via noncanonical routes. This kinase facilitates starvation adaptation by promoting processes such as DNA repair and decreasing oxidative damage, independent of its traditional role linked to protein synthesis inhibition.
When faced with nutrient scarcity, cells typically prioritize energy conservation by reducing protein synthesis, which constitutes up to 35 percent of cellular energy expenditure. Central to this regulation is eEF2K, which modulates the activity of eEF2—the factor responsible for translation elongation. Initially, it was assumed eEF2K's function during starvation was predominantly to suppress translation via phosphorylation of eEF2. Yet, studies involving EFK-1/eEF2K show this is only part of the story.
Research using EFK-1 deficient C. elegans has unveiled surprising insights. Unlike mammals, where translation blockage occurs during starvation through increased phosphorylation of eEF2, starved C. elegans maintains high levels of EEF-2 phosphorylation without the expected elevation during starvation stress responses. Comprehensive analysis demonstrated how EFK-1 operates independently of EEF-2 phosphorylation, taking advantage of alternate mechanisms to facilitate survival during periods of food scarcity.
One of EFK-1’s pivotal actions is the upregulation of genes involved in DNA repair processes, including nucleotide excision repair (NER) and base excision repair (BER). By activating these pathways, EFK-1 enhances the organism's ability to cope with oxidative damage—an increase often seen during prolonged starvation. Data revealed EFK-1 not only suppresses reactive oxygen species (ROS) accumulation, which can be debilitating to cellular integrity but also promotes mitochondrial health by repressing excessive oxygen consumption.
Importantly, EFK-1's signaling pathway connects to transcription factors, particularly the p53-like CEP-1 and bZIP family member ZIP-2. These factors are instrumental for the upregulation of cytoprotective and repair genes during starvation, enhancing organismal resistance to oxidative challenges. When EFK-1 was inactive or absent, the worms exhibited notable defects corresponding to higher susceptibility to starvation-induced stress.
To solidify this connection, the research included analyses of various EFK-1 associated mutants and examined how intertwined these factors are. The synergistic interactions unveiled through genetic assays confirmed CEP-1 and ZIP-2's roles as necessary partners to realize EFK-1’s starvation response potential.
With these discoveries, scientists are now prompted to rethink established models of how eEF2K functions under stress. Rather than focusing solely on translation elongation suppression, EFK-1 elucidates mechanisms promoting DNA repair and oxidative stress responses, which may also extend to cancers where similar stress adaptations allow cell survival under adverse conditions.
The work symbolizes promising potential pathways to exploit for enhancing resilience against nutrient deprivation—organizing stress adaptation on more versatile supports than previously conceived.
This research encourages additional explorations on the mechanistic involvement of EFK-1 beyond nutrient deprivation, pointing out its relevance for broader biological processes, including aging, metabolic adaptations, and oncogenesis.