State Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, Yunnan, China.
School of Agronomy and Life Sciences, Kunming University, Kunming, Yunnan, China.
PLoS Genet. 2021 Mar 3;17(3):e1009383. doi: 10.1371/journal.pgen.1009383. eCollection 2021 Mar.
As both host and pathogen require iron for survival, iron is an important regulator of host-pathogen interactions. However, the molecular mechanism by which how the availability of iron modulates host innate immunity against bacterial infections remains largely unknown. Using the metazoan Caenorhabditis elegans as a model, we demonstrate that infection with a pathogenic bacterium Salmonella enterica serovar Typhimurium induces autophagy by inactivating the target of rapamycin (TOR). Although the transcripts of ftn-1 and ftn-2 encoding two H-ferritin subunits are upregulated upon S. Typhimurium infection, the ferritin protein is kept at a low level due to its degradation mediated by autophagy. Autophagy, but not ferritin, is required for defense against S. Typhimurium infection under normal circumstances. Increased abundance of iron suppresses autophagy by activating TOR, leading to an increase in the ferritin protein level. Iron sequestration, but not autophagy, becomes pivotal to protect the host from S. Typhimurium infection in the presence of exogenous iron. Our results show that TOR acts as a regulator linking iron availability with host defense against bacterial infection.
由于宿主和病原体都需要铁才能生存，因此铁是宿主-病原体相互作用的重要调节剂。然而，铁的可用性如何调节宿主先天免疫抵抗细菌感染的分子机制在很大程度上仍然未知。我们使用后生动物秀丽隐杆线虫作为模型，证明感染致病性细菌沙门氏菌肠炎血清型 Typhimurium 通过使雷帕霉素靶蛋白（TOR）失活来诱导自噬。尽管编码两个 H 铁蛋白亚基的 ftn-1 和 ftn-2 的转录本在 S. Typhimurium 感染时上调，但由于自噬介导的降解，铁蛋白蛋白保持在低水平。在正常情况下，自噬而不是铁蛋白对于防御 S. Typhimurium 感染是必需的。铁含量的增加通过激活 TOR 抑制自噬，导致铁蛋白蛋白水平增加。在存在外源性铁的情况下，铁螯合而不是自噬对于保护宿主免受 S. Typhimurium 感染变得至关重要。我们的结果表明，TOR 作为一种调节剂，将铁的可用性与宿主抵抗细菌感染的防御联系起来。
