Kinases Mst1/2 Play An Important Role In Maintaining Homeostasis Of Macrophage Cellular ROS

Hippo pathway is an evolutionarily conserved pathway that is of great importance in many physiological processes including organ size control,tissue homeostasis and tumorigenesis.Core members of mammalian canonical Hippo pathway comprise kinases Mstl/2,Latsl/2 and downstream effectors Yap/TAZ.Recent studies have shown that kinases Mstl/2 also play a pivotal role in T cell proliferation,migration,differentiation,phagocytosis and inflammation.In innate immune system,phagocytes require abundant cellular reactive oxygen species(ROS)to destroy pathogenic microorganisms.However,if accumulated excessively or not eliminated in time,redundant ROS will inevitably exert cytotoxic effects,causing oxidative damage to nucleic acids,proteins and lipids and apoptosis.Despite existing mechanisms in non-immunocytes,it still remains incompletely understood about the underlying mechanism through which immune cells,especially phagocytes protect against oxidative damage.In this study we found that macrophages from Mst lfl/fl Mst2fl/fl Lyz-Cre(cDKO)mice exhibited higher basal ROS levels and more apoptotic events than those from Mst 1fl/flMst2fl/fl wild-type(WT)littermates,and the deficiencies were further rescued by NAC treatment.Following that,we found Mstl/2,served as a ROS sensor,was activated by cellular ROS and recruited from the cytosol to the mitochondrial outer membrane in WT BMDMs(bone marrow-derived macrophages),indicating that Mstl/2 might be involved in the antioxidant progress directly.Further,we found that Nrf2 was highly expressed in macrophage.The expression of Nrf2-dependent genes such as Gc/c,Gclm,Ho-1 and Nqo1 was significantly downregulated in cDKO macrophages.Moreover,Nrf2 deficient macrophages exhibited similar deficiencies with cDKO ones,which demonstrated that Nrf2 was likely to be the downstream antioxidant target of Mst1/2.In conclusion,Mstl/2-null macrophages exhibit increased susceptibility to apoptosis for their incapability of clearing redundant ROS,while WT BMDMs could sense cellular ROS levels,activate Mst-Nrf2 signaling and cease potential oxidative damage,thus maintain their own redox homeostasis.