A Plasmodium falciparum molecular mechanism of heme binding and sensitivity to artemisinins

A Plasmodium falciparum molecular mechanism of heme binding and sensitivity to artemisinins | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A Plasmodium falciparum molecular mechanism of heme binding and sensitivity to artemisinins Souvik Bhattacharjee, Smritikana Dutta, Mohammad Faaiz, Saikat Bhattacharjee, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7699689/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Heme is critical to activating artemisinins (ARTs), drugs essential for malaria control. Plasmodium falciparum malaria Kelch13 (K13) binds heme in vitro , but the consequences for in vivo functions remain unknown. As taut regulation of free-heme levels is not feasible in infected erythrocytes, we developed human Du145 cells as a model to study molecular properties of K13 at biological heme concentrations. We show that K13 levels are exquisitely responsive to nanomolar amounts of heme. Heme stabilizes K13 with molecular specificity, raises its oxidative-stress responses and association with autophagic-endosomes. Targeted disruption of lysosomal autophagy further increases K13 levels to fuel ART-induced redox-cell death that is proportional to K13 intensities at physiological heme levels. K13’s kelch-domain confers both heme and ART responsiveness to its mammalian orthologue KEAP1. These data suggest a novel molecular mechanism of K13-heme binding regulating ART-sensitization and power of models to study frontiers of pro-oxidant stress. Biological sciences/Cell biology/Mechanisms of disease Biological sciences/Biochemistry/Proteins/Proteome Full Text Additional Declarations There is NO Competing Interest. Supplementary Files DuttaetalSUPPLEMENTARYDATA240925.pdf Dataset 1 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7699689","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":522400510,"identity":"3a52fc0d-13b1-4ac9-9dab-86dc771204fb","order_by":0,"name":"Souvik 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