Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, China.
Department of Biochemistry, Center for Molecular Biomedicine (CMB), Friedrich Schiller University Jena, Jena, Germany.
mBio. 2024 Oct 16;15(10):e0075624. doi: 10.1128/mbio.00756-24. Epub 2024 Sep 17.
Phagocytosis of () followed by its integration into the matured lysosome is critical in the host defense against tuberculosis. How 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. 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 , while overexpression significantly increased the host defense against , as determined by bacterial burden and inflammatory-histopathological damage in the lung. Mechanistically, we demonstrated that SIRT7 limits 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 infection and proposes a potential target for tuberculosis treatment.IMPORTANCETuberculosis (TB), caused by (), remains a significant global health issue. Critical to macrophages' defense against is phagocytosis, governed by the actin cytoskeleton. Previous research has revealed that 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: 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 . This insight into the dynamic between host and pathogen in TB not only broadens our understanding but also opens new avenues for therapeutic development.
吞噬作用 () 随后将其整合到成熟的溶酶体中，对于宿主抵抗结核病至关重要。仍然不清楚 如何逃避这种免疫攻击。在这项研究中，我们揭示了一种新的调节机制，即 SIRT7 通过调节 RAC1 激活来调节细胞骨架重塑。我们发现，结核病患者的 CD14 单核细胞中 SIRT7 的表达显著降低。感染在 mRNA 和蛋白水平上均使巨噬细胞中的 SIRT7 表达减少。SIRT7 缺乏会损害依赖肌动蛋白细胞骨架的巨噬细胞吞噬作用、LC3II 表达和杀菌活性。在小鼠结核病模型中，SIRT7 缺乏对宿主抵抗 的不利影响，而 过表达则显著增加了宿主对 的防御能力，这通过肺部的细菌负荷和炎症组织病理学损伤来确定。在机制上，我们证明 SIRT7 通过与 RAC1 直接相互作用并激活它来限制 感染，通过这种方式调节细胞骨架重塑。因此，我们得出结论，SIRT7 通过 RAC1 调节细胞骨架重塑，在宿主感染期间的宿主反应中至关重要，并为结核病治疗提出了一个潜在的靶点。
重要提示：结核病（TB）由 （）引起，仍然是一个重大的全球健康问题。吞噬作用是巨噬细胞抵抗 的关键，由肌动蛋白细胞骨架控制。先前的研究表明， 操纵和破坏宿主的肌动蛋白网络，但具体机制尚不清楚。我们的研究确定了 SIRT7 在这方面的关键作用： 感染导致 SIRT7 表达降低，进而降低 RAC1 激活，从而损害肌动蛋白依赖性吞噬作用。我们研究的意义在于 SIRT7 直接与 Rac 家族小 GTP 酶 1（RAC1）结合并激活它，从而促进有效的吞噬作用和 的消除。对结核病中宿主与病原体之间动态关系的这一深入了解不仅拓宽了我们的理解，还为治疗开发开辟了新途径。
