TAOK3, also known as thousand-and-one amino acid kinase 3 or MAP3K18, is a serine/threonine kinase belonging to the STE20 kinase family and the MAP kinase family. It is involved in multiple biological pathways, including TCR signaling, autophagy regulation, and lipid metabolism, and is crucial for various physiological and pathological processes [1,2,4]. Genetic models, such as KO/CKO mouse models, have been valuable in studying its functions.

In Taok3 -/- mice, several phenotypes were observed. In obesity, ST2+ Tregs in visceral adipose tissue were upregulated, and metabolic dysfunction was attenuated, suggesting TAOK3 inhibits adipose tissue Tregs and regulates immunometabolism [2]. In a house dust mite-induced asthma mouse model, Taok3 -/- mice failed to develop salient features of asthma due to defects in both adaptive DC-mediated TH2 activation and innate ILC2 function, identifying Taok3 as a potential drug target for type 2-high asthma [3]. In NAFLD studies, while in vitro silencing of TAOK3 in hepatocytes affected lipid deposition, Taok3 knockout mice showed no attenuation in diet-induced NAFLD development, likely due to activation of related STE20-type kinases as a compensatory response [4,6]. In T cells, TAOK3-deficient human T cells had impaired LCK-dependent TCR signaling [5].

In conclusion, TAOK3 is a key regulator in multiple biological processes. Model-based research, especially KO/CKO mouse models, has revealed its role in obesity-related immunometabolism, asthma development, and NAFLD. These findings provide insights into the underlying mechanisms of these diseases and potential therapeutic targets related to TAOK3.

References:

1. Ormonde, João V S, Nie, Yan, Madrenas, Joaquin. . TAOK3, a Regulator of LCK-SHP-1 Crosstalk during TCR Signaling. In Critical reviews in immunology, 39, 59-81. doi:10.1615/CritRevImmunol.2019030480. https://pubmed.ncbi.nlm.nih.gov/31679194/

2. Maes, Bastiaan, Fayazpour, Farzaneh, Catrysse, Leen, Janssens, Sophie, Lambrecht, Bart N. 2023. STE20 kinase TAOK3 regulates type 2 immunity and metabolism in obesity. In The Journal of experimental medicine, 220, . doi:10.1084/jem.20210788. https://pubmed.ncbi.nlm.nih.gov/37347461/

3. Maes, Bastiaan, Smole, Ursula, Vanderkerken, Matthias, Lambrecht, Bart N, Hammad, Hamida. 2021. The STE20 kinase TAOK3 controls the development of house dust mite-induced asthma in mice. In The Journal of allergy and clinical immunology, 149, 1413-1427.e2. doi:10.1016/j.jaci.2021.08.020. https://pubmed.ncbi.nlm.nih.gov/34506849/

4. Xia, Ying, Caputo, Mara, Cansby, Emmelie, Blüher, Matthias, Mahlapuu, Margit. 2021. STE20-type kinase TAOK3 regulates hepatic lipid partitioning. In Molecular metabolism, 54, 101353. doi:10.1016/j.molmet.2021.101353. https://pubmed.ncbi.nlm.nih.gov/34634521/

5. Ormonde, João V S, Li, Zhigang, Stegen, Camille, Madrenas, Joaquín. 2018. TAOK3 Regulates Canonical TCR Signaling by Preventing Early SHP-1-Mediated Inactivation of LCK. In Journal of immunology (Baltimore, Md. : 1950), 201, 3431-3442. doi:10.4049/jimmunol.1800284. https://pubmed.ncbi.nlm.nih.gov/30373850/

6. Xia, Ying, Andersson, Emma, Caputo, Mara, Blüher, Matthias, Mahlapuu, Margit. 2023. Knockout of STE20-type kinase TAOK3 does not attenuate diet-induced NAFLD development in mice. In Molecular medicine (Cambridge, Mass.), 29, 138. doi:10.1186/s10020-023-00738-y. https://pubmed.ncbi.nlm.nih.gov/37864157/