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Characterization of the ATG8-conjugation system in 2 Plasmodium species with special focus on the liver stage: possible linkage between the apicoplastic and autophagic systems?

ABSTRACT: Plasmodium parasites successfully colonize different habitats within mammals and mosquitoes, and adaptation to various environments is accompanied by changes in their organelle composition and size. Previously, we observed that during hepatocyte infection, Plasmodium discards organelles involved in invasion and expands those implicated in biosynthetic pathways. We hypothesized that this process is regulated by autophagy. Plasmodium spp. possess a rudimentary set of known autophagy-related proteins that includes the ortholog of yeast Atg8. In this study, we analyzed the activity of the ATG8-conjugation pathway over the course of the lifecycle of Plasmodium falciparum and during the liver stage of Plasmodium berghei. We engineered a transgenic P. falciparum strain expressing mCherry-PfATG8. These transgenic parasites expressed mCherry-PfATG8 in human hepatocytes and erythrocytes, and in the midgut and salivary glands of Anopheles mosquitoes. In all observed stages, mCherry-PfATG8 was localized to tubular structures. Our EM and colocalization studies done in P. berghei showed the association of PbATG8 on the limiting membranes of the endosymbiont-derived plastid-like organelle known as the apicoplast. Interestingly, during parasite replication in hepatocytes, the association of PbATG8 with the apicoplast increases as this organelle expands in size. PbATG3, PbATG7 and PbATG8 are cotranscribed in all parasitic stages. Molecular analysis of PbATG8 and PbATG3 revealed a novel mechanism of interaction compared with that observed for other orthologs. This is further supported by the inability of Plasmodium ATG8 to functionally complement atg8Δ yeast or localize to autophagosomes in starved mammalian cells. Altogether, these data suggests a unique role for the ATG8-conjugation system in Plasmodium parasites.

SUBMITTER: Jayabalasingham B

PROVIDER: S-EPMC5396099 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Systemic light chain amyloidosis is a rare and life-threatening disorder, for which accurate risk stratification is crucial. Current cardiac staging systems (MAYO2004, MAYO3b, and MAYO2012) are mainly based on biomarkers, which have uncertain reliability in the context of atrial fibrillation, arrhythmia or pacemaker stimulation as well as renal insufficiency. We compared the performance of the established staging systems with particular regard to these comorbidities in 1,224 patients with systemic light chain amyloidosis diagnosed at our center from July 2002 until March 2017. We first characterized the subsets with an estimated glomerular filtration rate <50 mL/min/1.73 m2 (415 patients) and any kind of atrial arrhythmia (183 patients) as unique high-risk subgroups with similarly increased cardiac biomarkers (χ2-test, all P<0.001). This resulted in a shift towards higher risk stages and reduced median overall survival compared to those of patients with better kidney function or without atrial arrhythmia in univariate analyses (13 vs 46 months and 17 vs 53 months, respectively; both P<0.001). Performance analysis revealed that predictions in the entire cohort were least precise with the MAYO2004 staging system and most precise with the MAYO3b system. This performance pattern was almost preserved for patients with an estimated glomerular filtration rate <50 mL/min/1.73 m2, but less so for those with atrial arrhythmias. The MAYO3b staging system was most robust. Importantly, atrial arrhythmia retained its prognostic value in multivariable analysis including age, difference between involved and uninvolved free light chains, and any staging system, while estimated glomerular filtration rate <50 mL/min/1.73 m2 was not statistically significant in multivariable analysis with the MAYO3b staging system. In conclusion, our results favor the MAYO3b staging system due to its consistently best performance and retained applicability in the subgroups with atrial arrhythmia and estimated glomerular filtration rate <50 mL/min/1.73 m2.

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Characterization of the ATG8-conjugation system in 2 Plasmodium species with special focus on the liver stage: possible linkage between the apicoplastic and autophagic systems?

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