Construction of a Plasmodium falciparum Rab‐interactome identifies CK1 and PKA as Rab‐effector kinases in malaria parasites

Fathia Ben Rached,Hana Talabani,Carinne Ndjembo‐Ezougou,Syama Chandran,Markus Meissner,Pierre Bourdoncle,Utpal Tatu,Vrushali Dandavate,Hélène Yera,Gordon Langsley

doi:10.1111/boc.201100081

Abstract

Background informationThe pathology causing stages of the human malaria parasite Plasmodium falciparum reside within red blood cells that are devoid of any regulated transport system. The parasite, therefore, is entirely responsible for mediating vesicular transport within itself and in the infected erythrocyte cytoplasm, and it does so in part via its family of 11 Rab GTPases. Putative functions have been ascribed to Plasmodium Rabs due to their homology with Rabs of yeast, particularly with Saccharomyces that has an equivalent number of rab/ypt genes and where analyses of Ypt function is well characterized.ResultsRabs are important regulators of vesicular traffic due to their capacity to recruit specific effectors. In order to identify P. falciparum Rab (PfRab) effectors, we first built a Ypt-interactome by exploiting genetic and physical binding data available at the Saccharomyces genome database (SGD). We then constructed a PfRab-interactome using putative parasite Rab-effectors identified by homology to Ypt-effectors. We demonstrate its potential by wet-bench testing three predictions; that casein kinase-1 (PfCK1) is a specific Rab5B interacting protein and that the catalytic subunit of cAMP-dependent protein kinase A (PfPKA-C) is a PfRab5A and PfRab7 effector.ConclusionsThe establishment of a shared set of physical Ypt/PfRab-effector proteins sheds light on a core set Plasmodium Rab-interactants shared with yeast. The PfRab-interactome should benefit vesicular trafficking studies in malaria parasites. The recruitment of PfCK1 to PfRab5B+ and PfPKA-C to PfRab5A+ and PfRab7+ vesicles, respectively, suggests that PfRab-recruited kinases potentially play a role in early and late endosome function in malaria parasites.

Highlights

There aremore than 225 million cases of malaria each year that result in 800000 deaths
We constructed a P. falciparum Rab (PfRab)-interactome using putative parasite Rab-effectors identified by homology to Ypt-effectors
We demonstrate its potential by wet-bench testing three predictions; that casein kinase-1 (PfCK1) is a specific Rab5B interacting protein and that the catalytic subunit of cAMP-dependent protein kinase A (PfPKA-C) is a PfRab5A and PfRab7 effector

Summary

Introduction

One reason that this apicomplexa parasite is such a successful pathogen is that it resides within red bloods cells that are MHC class I and class II negative and so are unable to present parasite-derived peptides to the human immune system. Plasmodium has to import and export substances to and from its own organelles (Kats et al, 2008) and across its own parasite plasma membrane It faces the challenge of importing and exporting molecules across the parasitophorous vacuole membrane within which it resides and across the infected host cell plasma membrane (Hanssen et al, 2010; Gruring et al, 2011). The pathology causing stages of the human malaria parasite Plasmodium falciparum reside within red blood cells that are devoid of any regulated transport system. Putative functions have been ascribed to Plasmodium Rabs due to their homology with Rabs of yeast, with Saccharomyces that has an equivalent number of rab/ypt genes and where analyses of Ypt function is well characterized

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Conclusion