Eif2ak2, also known as protein kinase R (PKR), is a key enzyme that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), orchestrating the cellular stress response. It is involved in multiple pathways such as the endoplasmic reticulum stress response [3,4]. It plays a significant role in various biological processes including immune response and has been associated with diseases like systemic lupus erythematosus (SLE) [5]. Gene knockout models can be valuable for studying its functions in vivo.

In Eif2ak2 gene knockdown mice, the inhibitory effect of berberine (BBR) on the secretion of inflammatory cytokines IL-1β, IL-6, IL-18 and TNF-α was obviously attenuated, indicating an Eif2ak2-dependent anti-inflammatory efficacy of BBR [1]. This shows that Eif2ak2 is crucial in BBR's anti-inflammatory network mechanism. In septic acute kidney injury, Eif2ak2 directly targets absent in melanoma 2 (AIM2), positively regulating its expression and promoting PANoptosis, an inflammatory programmed cell death [2].

In conclusion, Eif2ak2 is essential in regulating the cellular stress response and is involved in multiple biological processes and disease conditions. Gene knockdown mouse models have revealed its significance in inflammation-related disorders and septic acute kidney injury, contributing to our understanding of these disease mechanisms and potentially guiding the development of new therapeutic strategies.

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. 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/

3. 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/

4. 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/

5. Ge, Lan, Zhang, Yuhong, Zhao, Xingwang, Zhang, Yi, You, Yi. 2021. EIF2AK2 selectively regulates the gene transcription in immune response and histones associated with systemic lupus erythematosus. In Molecular immunology, 132, 132-141. doi:10.1016/j.molimm.2021.01.030. https://pubmed.ncbi.nlm.nih.gov/33588244/