Mycobacterium tuberculosis exploits SIRT2 to trap iron for its intracellular survival

Iron is a critical nutrient for all organisms ranging from bacteria to humans. Ensuring control of this strategic vital resource significantly influences the dynamics of the struggle between host and invading pathogen. Mycobacterium tuberculosis (Mtb), the causative agent of the pulmonary disease tuberculosis (TB), has been plaguing humans for millennia and has evolved to successfully persist and multiply within host cells evading the mammalian immune defences. Invading Mtb appropriates host iron for its survival while the host innate immune response attempts to prevent its stores of this strategic mineral from being appropriated. SIRT2 is a member of the Sirtuin family. These are evolutionary conserved NAD⁺-dependent deacetylases involved in various cellular processes including regulation of cellular iron homeostasis. Upon Mtb infection of macrophages, SIRT2 expression is enhanced and it translocates from cytosol to nucleus. This is accompanied with a breakdown of the host's iron restriction strategy that compromises host defence mechanisms. However, the underlying mechanism as to how invading Mtb exploits SIRT2 for commandeering host iron remains unknown. In the current study, we report that the decreased bacillary load in cells wherein SIRT2 had been chemically inhibited or knocked down is due to diminished availability of iron. Inhibition or knockdown of SIRT2 in infected cells displays differential modulation of iron import and export proteins suggesting an ongoing struggle by host to limit the bioavailability of iron to pathogen. Flow cytometry analysis of infected macrophages revealed that these cells utilize a non-canonical pathway for evacuation of intracellular iron. This involves the recruitment of a specific pleioform of the moonlighting protein glyceraldehyde-3 phosphate dehydrogenase (GAPDH) to cell surface for capture of iron transporter protein apo-transferrin. Collectively, our findings reveal the process of SIRT2-mediated iron regulation in Mtb pathogenesis and could provide leads for design of novel host-targeted therapeutics.