Given the enormous health burden of Tuberculosis, great effort has been invested into understanding the molecular mechanisms underpinning mycobacterial pathogenesis. Approximately 10% of the coding capacity of the Mycobacterium tuberculosis genome is dedicated to the PE/PPE family of proteins, a conserved set of functionally distinct proteins that contain a characteristic Pro-Glu (PE) or Pro-Pro-Glu (PPE) motif in their N-terminal region. One member, referred to here as PPVP, appears to be under the control of LirAB, a newly characterised two-component regulatory system of M. tuberculosis. RT-qPCR data demonstrates that ppvp is downregulated under acidic conditions in vitro, suggesting this protein may be important for adaptation to the macrophage phagosome. Overexpression of ppvp in recombinant Mycobacterium smegmatis, an avirulent relative of M. tuberculosis, is associated with increased survival, enhanced phagocytosis and immunomodulation in murine macrophages. Molecular tracking of PPVP using confocal microscopy indicates this protein localises to the nuclear membrane following internalisation of murine macrophages. Our work suggests a multi-functional role of PPVP which may mediate adherence and evasion of host-mediated immune factors.