Abstract
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.