{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T01:20:53Z","timestamp":1777166453267,"version":"3.51.4"},"reference-count":53,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T00:00:00Z","timestamp":1636588800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JC Bose fellowship","award":["DST\/21\/015"],"award-info":[{"award-number":["DST\/21\/015"]}]},{"name":"Arturo Falaschi ICGEB Predoctoral fellowship","award":["F\/KEN18-10"],"award-info":[{"award-number":["F\/KEN18-10"]}]},{"DOI":"10.13039\/501100001688","name":"International Centre for Genetic Engineering and Biotechnology","doi-asserted-by":"publisher","award":["DBT\/10\/026"],"award-info":[{"award-number":["DBT\/10\/026"]}],"id":[{"id":"10.13039\/501100001688","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Reduced sensitivity of the human malaria parasite, Plasmodium falciparum, to Artemisinin and its derivatives (ARTs) threatens the global efforts towards eliminating malaria. ARTs have been shown to cause ubiquitous cellular and genetic insults, which results in the activation of the unfolded protein response (UPR) pathways. The UPR restores protein homeostasis, which otherwise would be toxic to cellular survival. Here, we interrogated the role of DNA-damage inducible protein 1 (PfDdi1), a unique proteasome-interacting retropepsin in mediating the actions of the ARTs. We demonstrate that PfDdi1 is an active A2 family protease that hydrolyzes ubiquitinated proteasome substrates. Treatment of P. falciparum parasites with ARTs leads to the accumulation of ubiquitinated proteins in the parasites and blocks the destruction of ubiquitinated proteins by inhibiting the PfDdi1 protease activity. Besides, whereas the PfDdi1 is predominantly localized in the cytoplasm, exposure of the parasites to ARTs leads to DNA fragmentation and increased recruitment of the PfDdi1 into the nucleus. Furthermore, we show that Ddi1 knock-out Saccharomycescerevisiae cells are more susceptible to ARTs and the PfDdI1 protein robustly restores the corresponding functions in the knock-out cells. Together, these results show that ARTs act in multiple ways; by inducing DNA and protein damage and might be impairing the damage recovery by inhibiting the activity of PfDdi1, an essential ubiquitin-proteasome retropepsin.<\/jats:p>","DOI":"10.3390\/pathogens10111465","type":"journal-article","created":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T23:04:46Z","timestamp":1636671886000},"page":"1465","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Artemisinin Binds and Inhibits the Activity of Plasmodium falciparum Ddi1, a Retroviral Aspartyl Protease"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2462-139X","authenticated-orcid":false,"given":"Noah Machuki","family":"Onchieku","sequence":"first","affiliation":[{"name":"Malaria Biology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonam","family":"Kumari","sequence":"additional","affiliation":[{"name":"Yeast Biofuel Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajan","family":"Pandey","sequence":"additional","affiliation":[{"name":"Translational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2133-3704","authenticated-orcid":false,"given":"Vaibhav","family":"Sharma","sequence":"additional","affiliation":[{"name":"Malaria Biology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohit","family":"Kumar","sequence":"additional","affiliation":[{"name":"Yeast Biofuel Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arunaditya","family":"Deshmukh","sequence":"additional","affiliation":[{"name":"Malaria Biology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inderjeet","family":"Kaur","sequence":"additional","affiliation":[{"name":"Malaria Biology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asif","family":"Mohmmed","sequence":"additional","affiliation":[{"name":"Parasite Cell Biology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7548-8835","authenticated-orcid":false,"given":"Dinesh","family":"Gupta","sequence":"additional","affiliation":[{"name":"Translational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0797-7378","authenticated-orcid":false,"given":"Daniel","family":"Kiboi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Jomo Kenyatta University of Agriculture and Technology, Nairobi P.O. Box 62000-00200, Kenya"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1224-8789","authenticated-orcid":false,"given":"Naseem","family":"Gaur","sequence":"additional","affiliation":[{"name":"Yeast Biofuel Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7384-6280","authenticated-orcid":false,"given":"Pawan","family":"Malhotra","sequence":"additional","affiliation":[{"name":"Malaria Biology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,11]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2019). 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