Model of DHA-mediated killing of P. falciparum. Activated ART (ART*) initiates a multi-pronged assault on protein homeostasis by damaging and unfolding proteins, preventing folding of newly synthesised proteins and inhibiting the proteasome (toxicity indicated with red bar). Activation of the ER Stress response, attenuates translation. Prolonged activation of the ER Stress response, and accumulation of toxic polyubiquitinated substrates (S) eventually leads to cell death. Other proteasome inhibitors also cause accumulation of polyubiquitinated proteins and parasite killing (Epoxomicin (Epo), b-AP15, and RA190). Inhibition of the E1/E2/E3 ubiquitin machinery (C1 or MLN4924) or ablation of protein synthesis (cycloheximide, CHX), prevents accumulation of polyubiquitinated proteins and enables cell survival (rescue indicated with green bar). In ART resistant parasites, defective presentation of proteins for polyubiquitination, may enable cell survival (15) (PDF) Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome. Bridgford JL, Xie SC, Cobbold SA, Pasaje CFA, Herrmann S, Yang T, Gillett DL, Dick LR, Ralph SA, Dogovski C, Spillman NJ, Tilley L. Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome. Nat Commun. 2018 9(1):3801.