Eif2ak2, also known as protein kinase R (PKR), is an IFN-stimulated gene. It encodes a kinase that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), thus orchestrating the cellular stress response. It is involved in pathways such as endoplasmic reticulum stress response and is associated with the regulation of inflammation, immunity, and neurological function [2,4,5]. Gene knockout models can be valuable in studying its function.

In Eif2ak2 gene knockdown mice, the inhibitory effect of berberine on the secretion of inflammatory cytokines like IL-1β, IL-6, IL-18 and TNF-α was attenuated, highlighting its role in berberine-mediated anti-inflammatory effects [1]. In septic AKI models, Eif2ak2 induced PANoptosis through upregulating AIM2 in LPS-stimulated HK-2 cells, revealing its role in sepsis-induced acute kidney injury [3]. In patients with Eif2ak2 variants, expression studies in fibroblasts showed abnormally enhanced activation of the cellular stress response, indicating its role in the pathogenesis of early onset generalized dystonia [5].

In conclusion, Eif2ak2 plays essential roles in inflammation, immunity, and neurological function. Gene knockdown and other model-based research have revealed its significance in anti-inflammatory processes, sepsis-induced acute kidney injury, and the pathogenesis of dystonia. These findings contribute to understanding the underlying mechanisms of related diseases and may provide potential therapeutic targets.

References:

1. Wei, Wei, Zeng, Qingxuan, Wang, Yan, Jiang, Jiandong, Song, Danqing. 2022. Discovery and identification of EIF2AK2 as a direct key target of berberine for anti-inflammatory effects. In Acta pharmaceutica Sinica. B, 13, 2138-2151. doi:10.1016/j.apsb.2022.12.009. https://pubmed.ncbi.nlm.nih.gov/37250154/

2. Waller, Sophie E, Morales-Briceño, Hugo, Williams, Laura, Tchan, Michel, Fung, Victor S C. 2021. Possible EIF2AK2-Associated Stress-Related Neurological Decompensation with Combined Dystonia and Striatal Lesions. In Movement disorders clinical practice, 9, 240-244. doi:10.1002/mdc3.13384. https://pubmed.ncbi.nlm.nih.gov/35146062/

3. Wei, Siwei, Wu, Lei, Xiang, Zhen, Jiang, Liubing, Du, Zhen. 2024. EIF2AK2 protein targeted activation of AIM2-mediated PANoptosis promotes sepsis-induced acute kidney injury. In Renal failure, 46, 2403649. doi:10.1080/0886022X.2024.2403649. https://pubmed.ncbi.nlm.nih.gov/39311631/

4. Thomsen, Mirja, Lange, Lara M, Zech, Michael, Lohmann, Katja. 2023. Genetics and Pathogenesis of Dystonia. In Annual review of pathology, 19, 99-131. doi:10.1146/annurev-pathmechdis-051122-110756. https://pubmed.ncbi.nlm.nih.gov/37738511/

5. Kuipers, Demy J S, Mandemakers, Wim, Lu, Chin-Song, Bertoli-Avella, Aida M, Bonifati, Vincenzo. 2020. EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia. In Annals of neurology, 89, 485-497. doi:10.1002/ana.25973. https://pubmed.ncbi.nlm.nih.gov/33236446/