 In the human immune system, specialized cells called fagocytes identify bacteria and then capture these infectious pathogens within compartments called fagosomes. Inside these compartments, toxic reactive oxygen species, or ROS, destroy the bacterial cells. However, how fagocytes generate ROS at the right place and time to kill bacteria but not host cells is still unclear. A new study has helped clarify this process by identifying the enzymes MST1 and MST2 as vital regulators of immune system function, helping the body defend against bacterial infection. Fagocytes detect bacteria using toll-like receptors or TLRs, which recognize molecular patterns that are unique to invading pathogens. Once confined within fagosomes, the bacteria are killed by fagocytes using ROS from two sources, fagosomes and mitochondria. Fagosomes produce ROS in response to signaling factors such as RAC1. Mitochondria also generate ROS as a byproduct of energy production. Importantly, RAC1 can induce mitochondria to move near fagosomes through the formation of a complex between fagosomal and mitochondrial proteins. This positioning allows ROS from mitochondria to enter fagosomes, enhancing the destruction of bacteria by fagocytes. In this study, the researchers found that the simultaneous loss of the protein-modifying enzymes MST1 and MST2 in immune cells of mice resulted in repeated bacterial infection and early death. This finding prompted further study of the roles of MST1 and MST2 in the RAC1-mediated destruction of bacteria by fagocytes. For this purpose, the researchers used immune cells harvested from mouse bone marrow, a common model used to study immune cell function. Stimulating TLRs at the cell surface activated MST1, ultimately increasing ROS production. Activating MST1 and MST2 also moved mitochondria next to fagosomes by facilitating the formation of the Fagosome-Mitochondria protein complex. In the absence of MST1 and MST2, fagocytes largely retained their ability to engulf bacteria. However, their ability to align mitochondria with fagosomes, accumulate ROS in fagosomes and thus destroy the absorbed bacteria, was significantly reduced. However, in cells lacking MST1 and MST2, mutating RAC1 into a continually activated form restored the immune cell's ability to produce ROS and destroy bacteria. These findings indicate that when pathogens activate TLRs, MST1 and MST2 act through RAC1 to position mitochondria next to fagosomes and to promote ROS production in fagocytes, resulting in maximal destruction of bacteria. However, how TLRs activate MST1 and MST2 remains to be determined. Identifying this mechanism may reveal novel therapeutic targets to help fight off infections.