Stk4, also known as mammalian STE20-like kinase 1 (MST1/KRS2), is a serine/threonine kinase and a central member of the Hippo signaling pathway. It regulates various cellular processes such as cell proliferation, survival, and differentiation, and is crucial for immune responses [1,3,4]. Genetic models, like knockout (KO) or conditional knockout (CKO) mouse models, have been valuable in studying its functions.

In Treg cells, Stk4 deficiency, alone or combined with its homolog Stk3, leads to a fatal autoimmune lymphoproliferative disease in mice. TCR signaling in Treg cells induces Stk4's nuclear translocation, forming an Stk4-NF-κB p65-Foxp3 complex. Stk4-dependent phosphorylation of Foxp3 on serine-418 stabilizes this complex, regulating Foxp3-and p65-dependent transcriptional programs, and promoting Treg cell-mediated immune tolerance [1]. In adipocytes, genetic inactivation of Stk3 and Stk4 increases mitochondrial mass and function, stabilizes uncoupling protein 1 in beige adipose tissue, and confers resistance to high-fat diet-induced metabolic dysfunction. STK3 and STK4 increase adipocyte mitophagy, in part, by regulating the phosphorylation and dimerization of the mitophagy receptor BNIP3 [3]. In humans, STK4 deficiency results in an autosomal recessively inherited primary immunodeficiency, often associated with EBV-related lymphoproliferative disorders [2]. A patient with a novel STK4 frameshift mutation showed impaired innate immunity, with significantly reduced type I, II, and III interferon responses due to decreased phosphorylation of TBK1 and IRF3, and some indicators of impaired adaptive immunity [4].

In conclusion, Stk4 plays essential roles in immune regulation, especially in Treg cell activation and homeostasis, as well as in adipocyte metabolism regulation. Mouse models with Stk4 deficiency have revealed its significance in autoimmune and lymphoproliferative diseases, as well as in immunodeficiency conditions related to abnormal interferon production [1,2,3,4].

References:

1. Cui, Ye, Benamar, Mehdi, Schmitz-Abe, Klaus, Charbonnier, Louis-Marie, Chatila, Talal A. 2022. A Stk4-Foxp3-NF-κB p65 transcriptional complex promotes Treg cell activation and homeostasis. In Science immunology, 7, eabl8357. doi:10.1126/sciimmunol.abl8357. https://pubmed.ncbi.nlm.nih.gov/36149942/

2. Saglam, Arzu, Cagdas, Deniz, Aydin, Burca, Katipoglu, Kubra, Uner, Aysegul. 2021. STK4 deficiency and EBV-associated lymphoproliferative disorders, emphasis on histomorphology, and review of literature. In Virchows Archiv : an international journal of pathology, 480, 393-401. doi:10.1007/s00428-021-03147-w. https://pubmed.ncbi.nlm.nih.gov/34604912/

3. Cho, Yoon Keun, Son, Yeonho, Saha, Abhirup, Granneman, James G, Lee, Yun-Hee. 2021. STK3/STK4 signalling in adipocytes regulates mitophagy and energy expenditure. In Nature metabolism, 3, 428-441. doi:10.1038/s42255-021-00362-2. https://pubmed.ncbi.nlm.nih.gov/33758424/

4. Jørgensen, Sofie E, Al-Mousawi, Ali, Assing, Kristian, Jakobsen, Marianne A, Mogensen, Trine H. 2020. STK4 Deficiency Impairs Innate Immunity and Interferon Production Through Negative Regulation of TBK1-IRF3 Signaling. In Journal of clinical immunology, 41, 109-124. doi:10.1007/s10875-020-00891-7. https://pubmed.ncbi.nlm.nih.gov/33078349/