SIRT7 remodels the cytoskeleton <i>via</i> RAC1 to enhance host resistance to <i>Mycobacterium tuberculosis</i>

Phagocytosis of <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) followed by its integration into the matured lysosome is critical in the host defense against tuberculosis. How <i>Mtb</i> escapes this immune attack remains elusive. In this study, we unveiled a novel regulatory mechanism by which SIRT7 regulates cytoskeletal remodeling by modulating RAC1 activation. We discovered that SIRT7 expression was significantly reduced in CD14⁺ monocytes of TB patients. <i>Mtb</i> infection diminished SIRT7 expression by macrophages at both the mRNA and protein levels. SIRT7 deficiency impaired actin cytoskeleton-dependent macrophage phagocytosis, LC3II expression, and bactericidal activity. In a murine tuberculosis model, SIRT7 deficiency detrimentally impacted host resistance to <i>Mtb</i>, while <i>Sirt7</i> overexpression significantly increased the host defense against <i>Mtb</i>, as determined by bacterial burden and inflammatory-histopathological damage in the lung. Mechanistically, we demonstrated that SIRT7 limits <i>Mtb</i> infection by directly interacting with and activating RAC1, through which cytoskeletal remodeling is modulated. Therefore, we concluded that SIRT7, in its role regulating cytoskeletal remodeling through RAC1, is critical for host responses during <i>Mtb</i> infection and proposes a potential target for tuberculosis treatment.IMPORTANCETuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), remains a significant global health issue. Critical to macrophages' defense against <i>Mtb</i> is phagocytosis, governed by the actin cytoskeleton. Previous research has revealed that <i>Mtb</i> manipulates and disrupts the host's actin network, though the specific mechanisms have been elusive. Our study identifies a pivotal role for SIRT7 in this context: <i>Mtb</i> infection leads to reduced SIRT7 expression, which, in turn, diminishes RAC1 activation and consequently impairs actin-dependent phagocytosis. The significance of our research is that SIRT7 directly engages with and activates Rac Family Small GTPase 1 (RAC1), thus promoting effective phagocytosis and the elimination of <i>Mtb</i>. This insight into the dynamic between host and pathogen in TB not only broadens our understanding but also opens new avenues for therapeutic development.