Liu Jie, Zuo Zehua, Fattah Rasem, Finkel Toren, Leppla Stephen H, Liu Shihui
Aging Institute of University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
mBio. 2024 Dec 11;15(12):e0216024. doi: 10.1128/mbio.02160-24. Epub 2024 Nov 7.
causes anthrax through a combination of bacterial infection and toxemia. As a major virulence factor of , anthrax lethal toxin (LT) is a zinc-dependent metalloproteinase, exerting its cytotoxicity through proteolytic cleavage of the mitogen-activated protein kinase kinases, thereby shutting down the MAPK pathways. Anthrax lethal toxin induces host lethality mostly by targeting the cardiovascular system. Although the enzymatic activity and the molecular targets of LT have long been known, the detailed mechanisms underlying cellular/tissue/organ toxicity are still poorly understood. In this work, we sought to investigate the mechanism of LT-induced cellular damage in the cardiovascular system. We demonstrate for the first time that anthrax lethal toxin has potent inhibitory effects on the central metabolism of cardiomyocytes and endothelial cells. This is likely due to the observed downregulating of c-Myc expression through the toxin-induced inhibition of the ERK pathway. Since c-Myc is a master transcription factor controlling the expression of many rate-limiting metabolic enzymes in glycolysis and the tricarboxylic acid cycle, LT's downregulation of c-Myc may lead to the observed bioenergetic collapse, particularly, in cardiomyocytes. Since cardiac cell contraction requires continuous production of large amounts of ATP, potent inhibition of the bioenergetics of cardiomyocytes would be incompatible with life. Thus, LT-induced lethality through targeting cardiomyocytes and endothelial cells appears to be a consequence of a bioenergetic collapse, likely due to the toxin's potent inhibitory activity on the MEK-ERK-c-Myc-metabolic/bioenergetic axis within these target cells of cardiovascular system.IMPORTANCEAnthrax lethal toxin (LT) is a major virulence factor of , the causative pathogen of anthrax disease. Anthrax lethal toxin is a metalloproteinase that cleaves and inactivates MEKs, thereby shutting down MAPK pathways, leading to host mortality primarily through targeting of the cardiovascular system. However, the detailed mechanisms underlying the toxin's cellular and tissue toxicity are still poorly understood. Here, we found that anthrax lethal toxin has potent inhibitory activity on glycolysis and oxidative phosphorylation of cardiomyocytes and endothelial cells. These effects appear to be the consequence of downregulation of c-Myc, a master transcription factor that controls many rate-limiting enzymes of glycolysis and the tricarboxylic acid cycle. With the high demand on energy for cardiac contraction, the potent inhibition of cardiomyocyte metabolism by LT would be incompatible with life. This work provides critical insights into why the cardiovascular system is the major target of LT-induced lethality.
通过细菌感染和毒血症的共同作用引发炭疽病。作为炭疽杆菌的主要毒力因子，炭疽致死毒素（LT）是一种锌依赖性金属蛋白酶，通过对丝裂原活化蛋白激酶激酶进行蛋白水解切割来发挥其细胞毒性，从而关闭丝裂原活化蛋白激酶（MAPK）信号通路。炭疽致死毒素主要通过作用于心血管系统导致宿主死亡。尽管LT的酶活性和分子靶点早已为人所知，但其导致细胞/组织/器官毒性的详细机制仍不清楚。在这项研究中，我们试图探究LT在心血管系统中诱导细胞损伤的机制。我们首次证明，炭疽致死毒素对心肌细胞和内皮细胞的中心代谢具有显著的抑制作用。这可能是由于观察到毒素通过抑制ERK信号通路下调了c-Myc的表达。由于c-Myc是控制糖酵解和三羧酸循环中许多限速代谢酶表达的主要转录因子，LT对c-Myc的下调可能导致观察到的生物能量代谢崩溃，尤其是在心肌细胞中。由于心肌细胞收缩需要持续产生大量ATP，对心肌细胞生物能量代谢的强烈抑制将与生命不相容。因此，LT通过靶向心肌细胞和内皮细胞诱导死亡似乎是生物能量代谢崩溃的结果，这可能是由于毒素对心血管系统这些靶细胞内的MEK-ERK-c-Myc-代谢/生物能量轴具有强大的抑制活性。
重要性
炭疽致死毒素（LT）是炭疽病病原体炭疽杆菌的主要毒力因子。炭疽致死毒素是一种金属蛋白酶，可切割并使MEK失活，从而关闭MAPK信号通路，主要通过作用于心血管系统导致宿主死亡。然而，毒素导致细胞和组织毒性的详细机制仍不清楚。在这里，我们发现炭疽致死毒素对心肌细胞和内皮细胞的糖酵解和氧化磷酸化具有强大的抑制活性。这些作用似乎是c-Myc下调的结果，c-Myc是控制糖酵解和三羧酸循环中许多限速酶的主要转录因子。由于心脏收缩对能量的需求很高，LT对心肌细胞代谢的强烈抑制将与生命不相容。这项研究为心血管系统为何是LT诱导死亡的主要靶点提供了关键见解。
