Mycobacterium tuberculosisexploits SIRT2 for iron acquisition to facilitate its intracellular survival

Abstract

AbstractIron availability is a critical factor for both bacteria and humans, and its availability significantly influences host-pathogen dynamics. AsMtbhas coevolved with the human race,Mtbrelentlessly tries to exploit iron from the tightly regulated iron machinery of host. Sirtuins are evolutionary conserved NAD+-dependent deacetylases involved in various cellular processes including infection. Notably, the cytosolic protein, Sirtuin 2 regulates cellular iron homeostasis in hepatocytes and afterMtbinfection, SIRT2 translocates to the nucleus leading to decreased protective immune response. However, the underlying mechanism as to howMtbexploits SIRT2 for iron acquisition remains unknown. In the current study, we observe that the decreased bacillary load in SIRT2 inhibited or knock down cells is due to low availability of iron to the bacilli. Inhibition or knockdown of SIRT2 inMtbinfected cells displays differential modulation of iron import and export proteins suggesting ongoing tussle by host to limit the bioavailability of iron to pathogen. More specifically, by flow cytometry analysis, we show significant upregulation of cell surface Apo Tf and GAPDH in infected SIRT2 inhibited macrophages. Thus, in SIRT2 depleted state, we delineate a different mechanism of iron export occurring through Apo Tf and GAPDH during infection in contrast to the classical iron exporter Fpn1. Collectively, our findings showed the importance of SIRT2-mediated iron regulation inMtbpathogenesis and can encourage designing of novel host-targeted therapeutics.