Characterization of a secretory hydrolase from sheds critical insight into host lipid utilization by .

causes tuberculosis in humans and predominantly infects alveolar macrophages. To survive inside host lesions and to evade immune surveillance, this pathogen has developed many strategies. For example, uses host-derived lipids/fatty acids as nutrients for prolonged persistence within hypoxic host microenvironments. imports these metabolites through its respective transporters, and in the case of host fatty acids, a pertinent question arises: does have the enzyme(s) for cleavage of fatty acids from host lipids? We show herein that a previously uncharacterized membrane-associated protein encoded by is conserved exclusively in actinomycetes, exhibits both lipase and protease activities, is secreted into macrophages, and catalyzes host lipid hydrolysis. In light of these functions, we annotated Rv2672 as mycobacterial secreted hydrolase 1 (Msh1). Furthermore, we found that this enzyme is up-regulated both in an model of hypoxic stress and in a mouse model of infection, suggesting that the pathogen requires Msh1 under hypoxic conditions. Silencing Msh1 expression compromised the ability of to proliferate inside lipid-rich foamy macrophages but not under regular culture conditions , underscoring Msh1's importance for persistence in lipid-rich microenvironments. Of note, this is the first report providing insight into the mechanism of host lipid catabolism by an enzyme, augmenting our current understanding of how meets its nutrient requirements under hypoxic conditions.