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 [4]. Genetic models, such as knockout (KO) mouse models, have been crucial in studying its functions.

In Treg cells, Stk4 deficiency, either 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 that promotes Treg cell activation and homeostasis [1]. In humans, STK4 deficiency is an autosomal recessively inherited primary immunodeficiency. Patients with STK4 deficiency often present with complex lymphoid proliferations, including EBV-associated lymphoproliferative disorders [2]. Additionally, in adipocytes, genetic inactivation of Stk3 and Stk4 increases mitochondrial mass and function, conferring resistance to metabolic dysfunction induced by high-fat diet feeding [3].

In conclusion, Stk4 plays essential roles in immune regulation, especially in Treg cell-mediated immune tolerance, and in metabolic regulation in adipocytes. Mouse models with Stk4 deficiency have been instrumental in revealing its functions in these areas, providing insights into autoimmune diseases, immunodeficiencies, and obesity-related diseases.