Eif2ak2, also known as protein kinase R (PKR), is a kinase that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), orchestrating the cellular stress response [4]. It is involved in multiple pathways, including endoplasmic reticulum stress response [3], and has been linked to the regulation of immune response and histone protein gene transcription, especially in relation to systemic lupus erythematosus [5].

In Eif2ak2 gene knockdown mice, the inhibitory effect of berberine on the secretion of inflammatory cytokines (IL-1β, IL-6, IL-18, and TNF-α) was significantly attenuated, demonstrating an Eif2ak2-dependent anti-inflammatory efficacy [1]. Also, Eif2ak2 depletion in in vitro models using LPS-stimulated HK2 cells showed reduced PANoptosis, indicating its role in sepsis-induced acute kidney injury through promoting AIM2-mediated PANoptosis [2].

In conclusion, Eif2ak2 is crucial for the cellular stress response and plays a significant role in inflammation-related disorders and sepsis-induced acute kidney injury. The gene knockdown mouse models have been instrumental in revealing its functions in these disease conditions, providing insights into potential therapeutic strategies for these diseases.

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/