Rosenthal Melissa, Ng Caroline
University of Nebraska Medical Center.
Res Sq. 2023 May 15:rs.3.rs-2926003. doi: 10.21203/rs.3.rs-2926003/v1.
The continued emergence and spread of resistance to artemisinins, the cornerstone of first line antimalarials, threatens significant gains made toward malaria elimination. Mutations in Kelch13 have been proposed to mediate artemisinin resistance by either reducing artemisinin activation via reduced parasite hemoglobin digestion or by enhancing the parasite stress response. Here, we explored the involvement of the parasite unfolded protein response (UPR) and ubiquitin proteasome system (UPS), vital to maintaining parasite proteostasis, in the context of artemisinin resistance. Our data show that perturbing parasite proteostasis kills parasites, early parasite UPR signaling dictate DHA survival outcomes, and DHA susceptibility correlates with impairment of proteasome-mediated protein degradation. These data provide compelling evidence toward targeting the UPR and UPS to overcome existing artemisinin resistance.
青蒿素是一线抗疟药物的基石，对其耐药性的持续出现和传播，威胁着在疟疾消除方面取得的重大进展。有人提出，Kelch13中的突变通过减少寄生虫血红蛋白消化从而降低青蒿素激活，或通过增强寄生虫应激反应来介导青蒿素耐药性。在此，我们探讨了在青蒿素耐药背景下，对维持寄生虫蛋白质稳态至关重要的寄生虫未折叠蛋白反应（UPR）和泛素蛋白酶体系统（UPS）所起的作用。我们的数据表明，扰乱寄生虫蛋白质稳态会杀死寄生虫，早期寄生虫UPR信号决定双氢青蒿素（DHA）的存活结果，并且DHA敏感性与蛋白酶体介导的蛋白质降解受损相关。这些数据为靶向UPR和UPS以克服现有的青蒿素耐药性提供了有力证据。
