Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, China.
Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China.
J Clin Invest. 2023 Apr 17;133(8):e159941. doi: 10.1172/JCI159941.
Ferritin, a key regulator of iron homeostasis in macrophages, has been reported to confer host defenses against Mycobacterium tuberculosis (Mtb) infection. Nuclear receptor coactivator 4 (NCOA4) was recently identified as a cargo receptor in ferritin degradation. Here, we show that Mtb infection enhanced NCOA4-mediated ferritin degradation in macrophages, which in turn increased the bioavailability of iron to intracellular Mtb and therefore promoted bacterial growth. Of clinical relevance, the upregulation of FTH1 in macrophages was associated with tuberculosis (TB) disease progression in humans. Mechanistically, Mtb infection enhanced NCOA4-mediated ferritin degradation through p38/AKT1- and TRIM21-mediated proteasomal degradation of HERC2, an E3 ligase of NCOA4. Finally, we confirmed that NCOA4 deficiency in myeloid cells expedites the clearance of Mtb infection in a murine model. Together, our findings revealed a strategy by which Mtb hijacks host ferritin metabolism for its own intracellular survival. Therefore, this represents a potential target for host-directed therapy against tuberculosis.
铁蛋白是巨噬细胞中铁稳态的关键调节剂，据报道它能赋予宿主对结核分枝杆菌（Mtb）感染的防御能力。核受体共激活因子 4（NCOA4）最近被确定为铁蛋白降解的货物受体。在这里，我们表明 Mtb 感染增强了巨噬细胞中 NCOA4 介导的铁蛋白降解，这反过来又增加了细胞内 Mtb 可用铁的含量，从而促进了细菌生长。与临床相关的是，巨噬细胞中 FTH1 的上调与人类结核病（TB）疾病的进展有关。在机制上，Mtb 感染通过 p38/AKT1 和 TRIM21 介导的 NCOA4 的 E3 连接酶 HERC2 的蛋白酶体降解增强了 NCOA4 介导的铁蛋白降解。最后，我们证实髓样细胞中 NCOA4 的缺失加速了小鼠模型中 Mtb 感染的清除。总之，我们的研究结果揭示了 Mtb 劫持宿主铁蛋白代谢以维持其细胞内生存的策略。因此，这代表了针对结核病的宿主导向治疗的一个潜在靶点。
