Eukaryotic elongation factor 2 kinase EFK-1/eEF2K promotes starvation resistance in Caenorhabditis elegans

Cells and organisms frequently experience starvation. In response, they mount an evolutionarily conserved stress response to adapt and survive. A vital component in the mammalian starvation response is eukaryotic elongation factor 2 (eEF2) kinase (eEF2K), which suppresses translation in starvation by phosphorylating and inactivating the translation elongation driver eEF2. In C. elegans, the eEF2K ortholog efk-1 phosphorylates a conserved residue on EEF-2/eEF2 and is essential for L1 starvation survival, but how it promotes survival remains unclear. To study how efk-1 promotes starvation resistance, I used the efk-1(ok3609) mutant which I confirmed was functionally null and had diminished efk-1 mRNA expression and abolished EEF-2 T56 phosphorylation. Surprisingly, unlike in mammalian cells, EEF-2 T56 phosphorylation is constitutive in both fed and starved wild-type C. elegans and does not increase in starvation. Moreover, C. elegans strains engineered to lack EFK-1 kinase activity or EEF-2 T56 phosphorylation are indistinguishable from wild type with regards to their ability to survive and recover from starvation, suggesting an alternative, kinase-independent mechanism of efk-1. To map this noncanonical pathway, I identified two transcription factors, bZIP transcription factor family 2 (ZIP-2) and C. elegans p53-like protein 1 (CEP-1), which are also required for starvation resistance and function downstream in the efk-1 pathway. Transcriptomic profiling of efk-1, zip-2, and cep-1 mutants revealed that the three factors are jointly required for increased expression of DNA repair pathway genes during starvation. Specifically, efk-1 is required to upregulate nucleotide excision repair (NER) and base excision repair (BER) to increase resistance to oxidative DNA damage, which is linked to starvation-induced oxidative stress. Additionally, efk-1 prevents reactive oxygen species (ROS) accumulation in the cell, maintains mitochondrial physiology and morphology, and represses oxygen consumption, all of which may ameliorate oxidative stress during starvation. Overall, my study describes for the first time a noncanonical mechanism of efk-1-mediated starvation resistance that is independent from both kinase activity of EFK-1 and the phosphorylation status of EEF-2. Future studies may determine if this noncanonical EFK-1/eEF2K pathway is conserved in cancer cells, which will inform development of new therapeutic strategies targeting aberrant eEF2K activation in human cancers.