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 cell proliferation, survival, differentiation, and immune responses through canonical and non-canonical Hippo signaling pathways [4]. Gene knockout (KO) and conditional knockout (CKO) mouse models have been valuable in studying its functions.

In Treg cells, Stk4 deficiency, either alone or in combination with its homolog Stk3, leads to a fatal autoimmune lymphoproliferative disease in mice. TCR signaling in Treg cells induces Stk4 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. Stk4 deficiency causes decreased Treg cell p65 expression and nuclear translocation, impaired NF-κB p65-Foxp3 complex formation, and defective Treg cell activation [1]. In humans, STK4 deficiency is an autosomal recessively inherited primary immunodeficiency, often associated with EBV-associated lymphoproliferative disorders, presenting complex histopathology [2]. 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 metabolic dysfunction induced by high-fat diet feeding. STK3 and STK4 increase adipocyte mitophagy in part by regulating the phosphorylation and dimerization status of the mitophagy receptor BNIP3 [3].

In conclusion, Stk4 is essential for Treg cell-mediated immune tolerance, and its deficiency can lead to severe immunodeficiency-related diseases. KO and CKO mouse models have revealed its crucial roles in immune regulation and energy metabolism-related processes, highlighting its potential as a target for treating obesity-related diseases and immunodeficiency-associated disorders.

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/