<i><i>Plasmodium falciparum</i></i>ATG8 implicated in both autophagy and apicoplast formation

Tomlins, Andrew M.; Rached, Fathia Ben; Williams, Roderick; Proto, William R.; Coppens, Isabelle; Ruch, Ulrike; Gilberger, Tim‐Wolf; Coombs, Graham H.; Mottram, Jeremy C.; Müller, Sylke; Langsley, Gordon

doi:10.4161/auto.25832

Cited by 81 publications

(125 citation statements)

References 56 publications

Supporting

Mentioning

112

Contrasting

Order By: Relevance

“…Rab7 is a small GTP-binding protein important for late endosomal transport, lysosomal biogenesis and, hence, progression of autophagy. This view-point suggests that under starvation, P. falciparum may use the food vacuole for an autophagy-like process, and undergoes transcriptionally silent hibernation-like state, which might be responsible for the remodelling of subcellular organelles to remove dispensable cellular material during intra-erythrocytic growth [21]. In a similar study, Cervantes et al (2014) have shown that under mild nutrient starvation, autophagy cannot be induced in P. falciparum.…”

Section: Autophagy In Plasmodiummentioning

confidence: 97%

“…In another study, rapamycin has been shown to inhibit the growth of P. falciparum, in vitro, at concentrations of 7.2 µmol/L (IC 50 ) and 12.5 µmol/L (IC 90 ) [33]. Tomlins et al (2013) have shown that in the erythrocytic stage, under amino acid deprivation, PfAtg8-containing structures (likely autophagosomes) fuse with P. falciparum Rab7 (PfRab7)-containing vesicles (likely late endosomes) to generate acidified vesicles. These vesicles, in turn, fuse with the digestive vacuoles of parasite (the final lytic compartment) which resembles lysosomal network of higher eukaryotes.…”

Section: Autophagy In Plasmodiummentioning

confidence: 99%

“…Nevertheless, only the visualisation of autophagy vacuoles observed through electron microscopy does not confirm the occurrence of autophagy [20]. However, information is now available regarding the functioning of autophagy in P. falciparum despite the absence of a typical lysosome for fusion with autophagosomes [21].…”

Section: Autophagy In Plasmodiummentioning

confidence: 99%

“…Vesicular trafficking of haemoglobin and other nutrients from host erythrocytes to plasmodial food vacuole is also known as an important process for parasite survival, where the involvement of P. falciparum Atg8 (PfAtg8) has been suggested [25]. Prolonged treatment with chloroquine has been reported to result in the accumulation of such haemoglobin-containing vesicles, which do not fuse with digestive vacuoles, and result in the prevention of haemoglobin digestion and amino acid starvation of malaria parasite [21]. Under the treatment of autophagy inhibitors like chloroquine or wortmannin, no change was observed in the PfAtg8 localization [26].…”

Section: Autophagy In Plasmodiummentioning

confidence: 99%

“…PfAtg8 has been implicated in both autophagy and apicoplast maintenance [21]; however, the actual mechanism of PfAtg8 in apicoplast maintenance remains unknown. To understand the underlying mechanism, there is need to determine the effect of various inhibitors of apicoplast biosynthetic pathways on the growth of P. falciparum, sufficient or deficient in PfAtg8.…”

Section: Autophagy In Plasmodiummentioning

confidence: 99%

See 4 more Smart Citations

Malaria: Autophagy as a Potential Therapeutic Target

Singh¹,

Chakraborty²

2016

JPP

View full text Add to dashboard Cite

Malaria, where the causative agent Plasmodium is rapidly gaining resistance to practically all the antimalarial drugs in clinical use, requires the identification of new drug targets to enable the discovery of novel, more effective and safer drugs to treat the disease. Advancements in molecular techniques have provided the proof of existence of autophagy in Plasmodium; however, its role(s) in malaria is only becoming to be understood. Nevertheless, some of the recently explored dimensions of autophagy in Plasmodium have indicated its fairly larger role in parasite survival and growth. But then, autophagy is also essential for host cell survival and defence. There is thus need to explore chemotherapeutic strategies to specifically target autophagy in both the parasite and host. This review focuses on autophagy pathways in Plasmodium and in host with a view to identify autophagy-related new drug targets for the discovery of novel antimalarial drugs.

show abstract

Section: Autophagy In Plasmodiummentioning

confidence: 97%

Section: Autophagy In Plasmodiummentioning

confidence: 99%

Section: Autophagy In Plasmodiummentioning

confidence: 99%

Section: Autophagy In Plasmodiummentioning

confidence: 99%

Section: Autophagy In Plasmodiummentioning

confidence: 99%

See 3 more Smart Citations

Malaria: Autophagy as a Potential Therapeutic Target

Singh¹,

Chakraborty²

2016

JPP

View full text Add to dashboard Cite

show abstract

Targeting the Atg8 Conjugation Pathway for Novel Anti‐Apicomplexan Drug Discovery

Miller

Bosch

2016

Comprehensive Analysis of Parasite Biology: From Metabolism to Drug Discovery

View full text Add to dashboard Cite

Virtual Screening and Experimental Validation Identify Novel Inhibitors of the Plasmodium falciparum Atg8–Atg3 Protein–Protein Interaction

et al. 2016

View full text Add to dashboard Cite

New therapies are needed against malaria, a parasitic infection caused by Plasmodium falciparum, as drug resistance emerges against the current treatment, artemisinin. We previously characterized the Atg8-Atg3 protein-protein interaction (PPI), which is essential for autophagy and parasite survival. Herein we illustrate the use of virtual library screening to selectively block the PPI in the parasite without inhibiting the homologous interaction in humans by targeting the A-loop of PfAtg8. This A-loop is important for Atg3 binding in Plasmodium, but is absent from the human Atg8 homologues. In this proof-of-concept study, we demonstrate a shift in lipidation state of PfAtg8 and inhibition of P. falciparum growth in both blood- and liver-stage cultures upon drug treatment. Our results illustrate how in silico screening and structure-aided drug design against a PPI can be used to identify new hits for drug development. Additionally, as we targeted a region of Atg8 that is conserved within apicomplexans, we predict that our small molecule will have cross-reactivity against other disease-causing apicomplexans, such as Toxoplasma, Cryptosporidium, Theileria, Neospora, Eimeria, and Babesia.

show abstract

Plasmodium falciparumATG8 implicated in both autophagy and apicoplast formation

Cited by 81 publications

References 56 publications

Malaria: Autophagy as a Potential Therapeutic Target

Malaria: Autophagy as a Potential Therapeutic Target

Targeting the Atg8 Conjugation Pathway for Novel Anti‐Apicomplexan Drug Discovery

Virtual Screening and Experimental Validation Identify Novel Inhibitors of the Plasmodium falciparum Atg8–Atg3 Protein–Protein Interaction

Contact Info

Product

Resources

About