Eef2k, short for eukaryotic elongation factor 2 kinase, is a highly unusual α -kinase. It phosphorylates the threonine 56 residue of eEF2, negatively regulating the elongation step of protein synthesis, an energy-and amino-acid-consuming process. Its activity is regulated by multiple inputs, including inhibition by mTORC1 signaling. eEF2K is activated under stress conditions like energy or nutrient depletion. Given its role in protein synthesis regulation, genetic models such as KO mouse models are valuable for studying its functions [1,3].

Male Eef2k-knockout mice were generated using Nuclease technology. These mice exhibited normal fertility and development, with no differences in spermatogenesis, sperm counts, or germ cell apoptosis compared to wild-type mice, suggesting Eef2k is dispensable for male fertility [4]. In melanoma, high eEF2K expression correlated with better response to anti-PD-1 treatment. Mechanistically, eEF2K bound to and inactivated GSK3β, leading to PD-L1 stabilization and tumor immune evasion. Knockdown of eEF2K decreased PD-L1 expression, enhanced CD8+ T cell activity, and attenuated melanoma growth in vivo. Also, eEF2K inhibitor enhanced the efficacy of PD-1 mAb therapy in a melanoma mouse model [2].

In conclusion, Eef2k is a key regulator of protein synthesis. Model-based research, especially KO mouse models, has revealed its diverse roles. In male reproduction, it is not essential for fertility. In cancer, particularly melanoma, it plays a role in regulating the tumor immune microenvironment. Understanding Eef2k through these models provides insights into its functions in normal and disease conditions, potentially guiding the development of new therapeutic strategies for cancer treatment.