Regulation of macrophage function through cytoskeletal remodeling by Sirt7 and Miz1

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health challenge. Macrophages play a key role in controlling Mtb infection, yet Mtb can evade or disrupt their defenses. I found reduced SIRT7 and MIZ1 expression in the peripheral blood of TB patients, with deficiencies in Sirt7 and Miz1 impairing macrophage function. Mtb disrupts macrophage immune responses by interfering with the filamentous actin (F-actin) cytoskeleton, though the mechanisms remain unclear. My study revealed that Mtb suppresses Sirt7 expression, leading to reduced Rac1 activation and impaired F-actin-mediated phagocytosis. Notably, SIRT7 expression was significantly lower in the CD14+ monocytes of TB patients, and Mtb infection decreased Sirt7 expression in macrophages at both mRNA and protein levels. Sirt7 deficiency impaired bactericidal activity and actin cytoskeleton-dependent phagocytosis. In a murine TB model, Sirt7 deficiency weakened host resistance, while Sirt7 overexpression enhanced Mtb clearance, as evidenced by bacterial burden and lung histopathology. Mechanistically, Sirt7 directly interacts with and activates Rac1 to regulate cytoskeletal remodeling and limit Mtb infection. Additionally, Miz1 expression was lower in TB patients than in those with latent TB. The deletion of Miz1’s POZ domain affected macrophage morphology and function. Under IL-4, GM-CSF, and M-CSF stimulation, Miz1ΔPOZ BMDMs exhibited elongated tails, and upon LPS/IFNγ stimulation, they showed reduced size and phagocytic capacity. ChIP-Seq and experimental validation identified Miz1 as a regulator of Tuba1a, Tuba1b, and Tuba1c transcription. Prior studies suggest that Miz1 associates with microtubules to facilitate nuclear entry, and I found that macrophage morphological changes promote its nuclear localization. I propose that microtubule dynamics mediate Miz1 translocation to regulate tubulin gene transcription, essential for cytoskeletal remodeling and phagocytosis.