Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome

被引：202

作者：

Bridgford, Jessica L. ^{[1
]}

Xie, Stanley C. ^{[1
]}

Cobbold, Simon A. ^{[1
]}

Pasaje, Charisse Flerida A. ^{[1
]}

Herrmann, Susann ^{[1
]}

Yang, Tuo ^{[1
]}

Gillett, David L. ^{[1
]}

Dick, Lawrence R. ^{[2
]}

Ralph, Stuart A. ^{[1
]}

Dogovski, Con ^{[1
]}

Spillman, Natalie J. ^{[1
]}

Tilley, Leann ^{[1
]}

机构：

[1] Univ Melbourne, Mol Sci & Biotechnol Inst Bio21, Dept Biochem & Mol Biol, Melbourne, Vic 3010, Australia

[2] Takeda Pharmaceut Int Co, Oncol Clin R&D, Cambridge, MA 02139 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

英国医学研究理事会;

关键词：

RESISTANT PLASMODIUM-FALCIPARUM; INFECTED ERYTHROCYTES; KINASE; STRESS; SENSITIVITY; CAMBODIA; THERAPY; REVEALS; FAILURE; DESIGN;

D O I：

10.1038/s41467-018-06221-1

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Artemisinin and its derivatives (collectively referred to as ARTs) rapidly reduce the parasite burden in Plasmodium falciparum infections, and antimalarial control is highly dependent on ART combination therapies (ACTs). Decreased sensitivity to ARTs is emerging, making it critically important to understand the mechanism of action of ARTs. Here we demonstrate that dihydroartemisinin (DHA), the clinically relevant ART, kills parasites via a two-pronged mechanism, causing protein damage, and compromising parasite proteasome function. The consequent accumulation of proteasome substrates, i.e., unfolded/damaged and polyubiquitinated proteins, activates the ER stress response and underpins DHA-mediated killing. Specific inhibitors of the proteasome cause a similar build-up of polyubiquitinated proteins, leading to parasite killing. Blocking protein synthesis with a translation inhibitor or inhibiting the ubiquitin-activating enzyme, E1, reduces the level of damaged, polyubiquitinated proteins, alleviates the stress response, and dramatically antagonizes DHA activity.

引用

页数：9

共 53 条

[1] Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study [J].

Amaratunga, Chanaki ;

Lim, Pharath ;

Suon, Seila ;

Sreng, Sokunthea ;

Mao, Sivanna ;

Sopha, Chantha ;

Sam, Baramey ;

Dek, Dalin ;

Try, Vorleak ;

Amato, Roberto ;

Blessborn, Daniel ;

Song, Lijiang ;

Tullo, Gregory S. ;

Fay, Michael P. ;

Anderson, Jennifer M. ;

Tarning, Joel ;

Fairhurst, Rick M. .

LANCET INFECTIOUS DISEASES, 2016, 16 (03) :357-365

[2] A bis-Benzylidine Piperidone Targeting Proteasome Ubiquitin Receptor RPN13/ADRM1 as a Therapy for Cancer [J].

Anchoori, Ravi K. ;

Karanam, Balasubramanyam ;

Peng, Shiwen ;

Wang, Joshua W. ;

Jiang, Rosie ;

Tanno, Toshihiko ;

Orlowski, Robert Z. ;

Matsui, William ;

Zhao, Ming ;

Rudek, Michelle A. ;

Hung, Chien-fu ;

Chen, Xiang ;

Walters, Kylie J. ;

Roden, Richard B. S. .

CANCER CELL, 2013, 24 (06) :791-805

[3]

[Anonymous], 2015, WORLD MALARIA REPORT

[4] A molecular marker of artemisinin-resistant Plasmodium falciparum malaria [J].

Ariey, Frederic ;

Witkowski, Benoit ;

Amaratunga, Chanaki ;

Beghain, Johann ;

Langlois, Anne-Claire ;

Khim, Nimol ;

Kim, Saorin ;

Duru, Valentine ;

Bouchier, Christiane ;

Ma, Laurence ;

Lim, Pharath ;

Leang, Rithea ;

Duong, Socheat ;

Sreng, Sokunthea ;

Suon, Seila ;

Chuor, Char Meng ;

Bout, Denis Mey ;

Menard, Sandie ;

Rogers, William O. ;

Genton, Blaise ;

Fandeur, Thierry ;

Miotto, Olivo ;

Ringwald, Pascal ;

Le Bras, Jacques ;

Berry, Antoine ;

Barale, Jean-Christophe ;

Fairhurst, Rick M. ;

Benoit-Vical, Franoise ;

Mercereau-Puijalon, Odile ;

Menard, Didier .

NATURE, 2014, 505 (7481) :50-+

[5] Discovery of 7-Methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a Potent and Selective First-in-Class Inhibitor of Protein Kinase R (PKR)-like Endoplasmic Reticulum Kinase (PERK) [J].

Axten, Jeffrey M. ;

Medina, Jesus R. ;

Feng, Yanhong ;

Shu, Arthur ;

Romeril, Stuart P. ;

Grant, Seth W. ;

Li, William Hoi Hong ;

Heerding, Dirk A. ;

Minthorn, Elisabeth ;

Mencken, Thomas ;

Atkins, Charity ;

Liu, Qi ;

Rabindran, Sridhar ;

Kumar, Rakesh ;

Hong, Xuan ;

Goetz, Aaron ;

Stanley, Thomas ;

Taylor, J. David ;

Sigethy, Scott D. ;

Tomberlin, Ginger H. ;

Hassell, Annie M. ;

Kahler, Kirsten M. ;

Shewchuk, Lisa M. ;

Gampe, Robert T. .

JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (16) :7193-7207

[6] A rapid, reversible, and tunable method to regulate protein function in living cells using synthetic small molecules [J].

Banaszynski, Laura A. ;

Chen, Lin-chun ;

Maynard-Smith, Lystranne A. ;

Ooi, A. G. Lisa ;

Wandless, Thomas J. .

CELL, 2006, 126 (05) :995-1004

[7] Substrate-Assisted Inhibition of Ubiquitin-like Protein-Activating Enzymes: The NEDD8 E1 Inhibitor MLN4924 Forms a NEDD8-AMP Mimetic In Situ [J].

Brownell, James E. ;

Sintchak, Michael D. ;

Gavin, James M. ;

Liao, Hua ;

Bruzzese, Frank J. ;

Bump, Nancy J. ;

Soucy, Teresa A. ;

Milhollen, Michael A. ;

Yang, Xiaofeng ;

Burkhardt, Anne L. ;

Ma, Jingya ;

Loke, Huay-Keng ;

Lingaraj, Trupti ;

Wu, Dongyun ;

Hamman, Kristin B. ;

Spelman, James J. ;

Cullis, Courtney A. ;

Langston, Steven P. ;

Vyskocil, Stepan ;

Sells, Todd B. ;

Mallender, William D. ;

Visiers, Irache ;

Li, Ping ;

Claiborne, Christopher F. ;

Rolfe, Mark ;

Bolen, Joseph B. ;

Dick, Lawrence R. .

MOLECULAR CELL, 2010, 37 (01) :102-111

[8] Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance [J].

Cerqueira, Gustavo C. ;

Cheeseman, Ian H. ;

Schaffner, Steve F. ;

Nair, Shalini ;

McDew-White, Marina ;

Phyo, Aung Pyae ;

Ashley, Elizabeth A. ;

Melnikov, Alexandre ;

Rogov, Peter ;

Birren, Bruce W. ;

Nosten, Francois ;

Anderson, Timothy J. C. ;

Neafsey, Daniel E. .

GENOME BIOLOGY, 2017, 18

[9] A thiol probe for measuring unfolded protein load and proteostasis in cells [J].

Chen, Moore Z. ;

Moily, Nagaraj S. ;

Bridgford, Jessica L. ;

Wood, Rebecca J. ;

Radwan, Mona ;

Smith, Trevor A. ;

Song, Zhegang ;

Tang, Ben Zhong ;

Tilley, Leann ;

Xu, Xiaohong ;

Reid, Gavin E. ;

Pouladi, Mahmoud A. ;

Hong, Yuning ;

Hatters, Danny M. .

NATURE COMMUNICATIONS, 2017, 8

[10] Inhibition of proteasome deubiquitinating activity as a new cancer therapy [J].

D'Arcy, Padraig ;

Brnjic, Slavica ;

Olofsson, Maria Hagg ;

Fryknas, Marten ;

Lindsten, Kristina ;

De Cesare, Michelandrea ;

Perego, Paola ;

Sadeghi, Behnam ;

Hassan, Moustapha ;

Larsson, Rolf ;

Linder, Stig .

NATURE MEDICINE, 2011, 17 (12) :1636-U150

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