Casp4, also known as caspase-4, is a key player in pyroptosis, a form of programmed lytic cell death. It is involved in the non-canonical inflammasome pathway, and is an innate immune receptor for intracellular lipopolysaccharide (LPS) [5]. Casp4 is crucial for the body's response to certain bacterial infections and is associated with inflammation-related biological processes [6]. Genetic models, especially KO mouse models, have been instrumental in studying its function.

In transgenic hACE2 humanized mice, Casp11 (mouse homolog of Casp4) deficiency protected against SARS-CoV-2-induced disease development, with reduced mortality, increased pulmonary parenchymal area, and a lower clinical disease score, indicating that Casp4/11 promotes NLRP3 activation and exacerbates COVID-19 [1]. In gliomas, high expression of Casp4 was associated with a significantly lower survival rate, and it could influence immune cell infiltration, suggesting it could be a diagnostic biomarker and a potential therapeutic target [2]. In renal cell carcinoma, Casp4 was identified as an autophagy-pyroptosis-related gene, with high expression correlating with higher pathological staging and poorer prognosis [4]. In macrophages, Casp4-deficient cells showed a defect in autophagosome formation in response to Burkholderia cenocepacia infection, revealing a new role of Casp4 in regulating autophagy [3].

In conclusion, Casp4 is essential in pyroptosis, innate immune response to intracellular LPS, and regulation of autophagy. Gene-knockout mouse models have been crucial in revealing its role in diseases such as COVID-19, gliomas, and renal cell carcinoma. Understanding Casp4's function provides potential therapeutic targets for these diseases.

References:

1. Rodrigues, Tamara S, Caetano, Camila C S, de Sá, Keyla S G, de Oliveira, Renê D R, Zamboni, Dario S. . CASP4/11 Contributes to NLRP3 Activation and COVID-19 Exacerbation. In The Journal of infectious diseases, 227, 1364-1375. doi:10.1093/infdis/jiad037. https://pubmed.ncbi.nlm.nih.gov/36763010/

2. Tian, Guopeng, Li, Qiao, Niu, Liang, Yuan, Guoqiang, Pan, Yawen. 2023. CASP4 can be a diagnostic biomarker and correlated with immune infiltrates in gliomas. In Frontiers in oncology, 12, 1025065. doi:10.3389/fonc.2022.1025065. https://pubmed.ncbi.nlm.nih.gov/36713560/

3. Krause, Kathrin, Caution, Kyle, Badr, Asmaa, Gavrilin, Mikhail A, Amer, Amal O. 2018. CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection. In Autophagy, 14, 1928-1942. doi:10.1080/15548627.2018.1491494. https://pubmed.ncbi.nlm.nih.gov/30165781/

4. Li, Tao, Liu, Ning, Zhang, Guangyuan, Chen, Ming. . CASP4 and CASP8 as newly defined autophagy-pyroptosis-related genes associated with clinical and prognostic features of renal cell carcinoma. In Journal of cancer research and therapeutics, 18, 1952-1960. doi:10.4103/jcrt.jcrt_126_22. https://pubmed.ncbi.nlm.nih.gov/36647955/

5. Shi, Jianjin, Zhao, Yue, Wang, Yupeng, Hu, Liyan, Shao, Feng. 2014. Inflammatory caspases are innate immune receptors for intracellular LPS. In Nature, 514, 187-92. doi:10.1038/nature13683. https://pubmed.ncbi.nlm.nih.gov/25119034/

6. Kayagaki, Nobuhiko, Warming, Søren, Lamkanfi, Mohamed, Roose-Girma, Merone, Dixit, Vishva M. 2011. Non-canonical inflammasome activation targets caspase-11. In Nature, 479, 117-21. doi:10.1038/nature10558. https://pubmed.ncbi.nlm.nih.gov/22002608/