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    • Finally life expectancy was strongly reduced in STK

    2022-02-11

    Finally, life expectancy was strongly reduced in STK4-deficient patients. Even in those patients who received haematopoietic stem cell transplantation, the majority of patients died due to transplantation-related complications, raising the question whether MST1 expressed in nonhaematopoietic tissue might contribute to successful engraftment and restoration of immune function following haematopoietic stem cell transplantation. Of note, in some of the patients congenital malformations of the heart were documented [13].
    Role of MST1/2 in Lymphocytes Similar to patients with STK4 loss of function mutation, mice displayed lymphopenia with a reduction in splenic white pulp, a decreased number of peripheral CD4+ and CD8+ T cells, B220+ B cells, and absence of marginal zone PTC-209 [18]. Global deletion of Mst2 did not alter lymphocyte numbers. However additional elimination of Mst2 in the haematopoietic lineage (–VavCre) or in lymphocytes () led to an aggravated phenotype shown by a dramatically increased severity of lymphopenia compared to mice. This indicates that MST2 can partially compensate for the loss of MST1 19, 20. Murine MST1 is most abundant in lymphoid organs and crucial in T cell development and function including selection in the thymus, adhesion, migration, apoptosis, and lineage commitment [21]. The noncanonical Hippo pathway in lymphocyte development and function has been reviewed in detail before [21]. Therefore, we focus here only on the most recent findings concerning the functional role of MST1 in lymphocytes in humans and mice.
    Role of MST1/2 in Myeloid Cells Evidence that MST1 might play a role in myeloid cell function came from the first studies in STK4-deficient patients reporting increased susceptibility to bacterial infections paired with intermittent neutropenia and an elevated rate of neutrophil apoptosis, as mentioned earlier [13]. Another study showed a high rate of infections in -Cre mice also suggesting functional deficits in the myeloid lineage in the absence of MST1/2 in the mouse [19]. While lymphopenia and defective T cell function may explain a major part of the clinical manifestations, the impaired responses to acute infections implied additional defects in myeloid cell function 13, 14, 16, 17, 34, 35, 36. However, LFA-1-mediated functions, like slow neutrophil rolling and adhesion, were not affected in MST1-deficient mice [35]. In contrast, Mst1-deficient neutrophils showed a severe extravasation defect with neutrophils trapped within postcapillary venules, between the endothelial layer and the vascular basement membrane (BM), failing to penetrate the BM and thus being unable to extravasate to the site of inflammation. This impairs efficient host defence during bacterial infection, as has been described for other diseases with primary defects in leukocyte recruitment including leukocyte adhesion deficiency (LAD) I–III (Box 1) [35].
    Concluding Remarks and Future Perspectives Through its noncanonical pathways, the Hippo homologue MST1 (and to a lesser degree MST2) has recently emerged as an important regulator of leukocyte functions. This has been learnt from Mst1−/− and Mst2−/− mice as well as from conditional Mst1 and Mst2 double-deficient mice, which aggravated the phenotype of Mst1−/− mice. Finally, these findings are complemented by the growing number of studies from patients with Stk4 deficiency. These patients show a similar phenotype as Mst1−/− mice, although one major difference exists in the rate and early onset of severe infections observed in patients with Stk4 deficiency compared to Mst1−/− mice. The difference might at least in part be explained by the fact that mice are bred and held under specific pathogen-free conditions that reduces the risk for infections [59]. There is now growing evidence that MST1 has a strong and cell-type-specific influence on recruitment functions in immune cells. In neutrophils, MST1 is critical for triggering Rab27/JFC1-dependent mobilization of VLA-3, VLA-6, and neutrophil-elastase-containing vesicles to the neutrophil surface; a prerequisite for the penetration of the vascular basement membrane. In T cells, MST1 controls LFA-1-dependent adhesion and migration via mediating Rab13/DENND1C-dependent mobilisation of LFA-1-containing vesicles to the surface. These findings point towards a regulatory role of MST1 on vesicle trafficking by acting on distinct Rab-GEFs/effectors in a cell-type-specific fashion. Future studies are needed to further elucidate the molecular mechanisms of the interplay between MST1 and Rabs/Rab-GEFs/effectors in neutrophils and T cells. Furthermore, it would be interesting to expand these studies to other immune cells including monocytes, macrophages, and dendritic cells, where vesicle trafficking is also critical for their immune functions (see Outstanding Questions). These studies will shine new light on the diverse and cell-type-specific functions of MST1 in immunity and further establish the importance of MST1 in immune cell regulation.