An Alternative Autophagy-Related Mechanism of Chloroquine Drug Resistance in the Malaria Parasite

Kamil, Mohd; Atmaca, Habibe N; Unal, Sinem; Kına, Ümit Yaşar; Burak, Pinar; Deveci, Gözde; Yilmaz, Ilknur; Aly, A. S.

doi:10.1128/aac.00269-22

Cited by 3 publications

(1 citation statement)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Though we have only evaluated the level of BiP mRNA, the upregulation in its expression can still be considered as an indicator of ER stress in Pbtmem33(−) parasites (Figure S2b). Since ER stress results in the activation of ERAD and UPR, which in turn regulates cell death pathways like apoptosis and autophagy (Peng et al., 2021), we checked the mRNA expression of autophagy (ATGs) and apoptosis (metacaspases) related genes (Kamil et al., 2019; Kamil, Atmaca, et al., 2022; Vandana et al., 2019). Our preliminary qPCR data showed that TMEM33 deletion results in the generation of ER stress which upregulated the expression of autophagy‐related genes in the malaria parasites (Figure S2c); however, no effect was observed in the expression of apoptosis marker genes (Figure S2d).…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum localized TMEM33 domain‐containing protein is crucial for all life cycle stages of the malaria parasite

Kamil,

Kina,

Atmaca

et al. 2024

Molecular Microbiology

View full text Add to dashboard Cite

Endoplasmic reticulum (ER) plays a pivotal role in the regulation of stress responses in multiple eukaryotic cells. However, little is known about the effector mechanisms that regulate stress responses in ER of the malaria parasite. Herein, we aimed to identify the importance of a transmembrane protein 33 (TMEM33)‐domain‐containing protein in life cycle of the rodent malaria parasite Plasmodium berghei. TMEM33 is an ER membrane‐resident protein that is involved in regulating stress responses in various eukaryotic cells. A C‐terminal tagged TMEM33 was localized in the ER throughout the blood and mosquito stages of development. Targeted deletion of TMEM33 confirmed its importance for asexual blood stages and ookinete development, in addition to its essential role for sporozoite infectivity in the mammalian host. Pilot scale analysis shows that the loss of TMEM33 results in the initiation of ER stress response and induction of autophagy. Our findings conclude an important role of TMEM33 in the development of all life cycle stages of the malaria parasite, which indicates its potential as an antimalarial target.

show abstract

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum localized TMEM33 domain‐containing protein is crucial for all life cycle stages of the malaria parasite

Kamil,

Kina,

Atmaca

et al. 2024

Molecular Microbiology

View full text Add to dashboard Cite

show abstract

Drug-induced ER stress leads to induction of programmed cell death pathways of the malaria parasite

Unal,

Kina,

Kamil

et al. 2024

Parasitol Res

View full text Add to dashboard Cite

The rapid emergence of drug resistance against the mainstream antimalarial drugs has increased the need for development of novel drugs. Recent approaches have embarked on the repurposing of existing drugs to induce cell death via programmed cell death pathways. However, little is known about the ER stress response and programmed cell death pathways of the malaria parasite. In this study, we treated ex vivo Plasmodium berghei cultures with tunicamycin, 5-fluorouracil, and chloroquine as known stress inducer drugs to probe the transcriptional changes of autophagy and apoptosis-related genes (PbATG5, PbATG8, PbATG12, and PbMCA2). Treatments with 5-fluorouracil and chloroquine resulted in the upregulation of all analyzed markers, yet the levels of PbATG5 and PbATG12 were dramatically higher in chloroquine-treated ex vivo cultures. In contrast, tunicamycin treatment resulted in the downregulation of both PbATG8 and PbATG12, and upregulation of PbMCA2. Our results indicate that the malaria parasite responds to various ER stressors by inducing autophagy- and/or apoptosis-like pathways.

show abstract

Oleuropein mediated autophagy begets antimalarial drug resistance

Sharma,

Chaudhary,

Devi

et al. 2024

Front. Microbiol.

View full text Add to dashboard Cite

Drug resistance in Plasmodium falciparum presents a formidable challenge to the humanity. And, unavailability of an effective vaccine worsens the situation further. Autophagy is one of the mechanisms employed by parasite to evade drug pressure to survive. Autophagy induced by the P. falciparum in response to the oleuropein pressure may answer many questions related to the parasite survival as well as evolving drug tolerance. The survival/autophagy axis could be an important avenue to explore in order to address certain questions related to the evolution of drug resistance. In addition, humanized mouse model of P. falciparum infection could serve as an important preclinical tool to investigate the oleuropein-induced autophagy, potentially helping to dissect the mechanisms underlying the development of antimalarial drug resistance.

show abstract

An Alternative Autophagy-Related Mechanism of Chloroquine Drug Resistance in the Malaria Parasite

Cited by 3 publications

References 27 publications

Endoplasmic reticulum localized TMEM33 domain‐containing protein is crucial for all life cycle stages of the malaria parasite

Endoplasmic reticulum localized TMEM33 domain‐containing protein is crucial for all life cycle stages of the malaria parasite

Drug-induced ER stress leads to induction of programmed cell death pathways of the malaria parasite

Oleuropein mediated autophagy begets antimalarial drug resistance

Contact Info

Product

Resources

About