IBIS1

IBIS1 (PBANKA_1365500) is a PEXEL/HT-containing exported protein of Plasmodium berghei that marks dynamic parasite-induced membranous compartments at the parasite/host interface across both liver and blood stages (PMID:22329949). In infected erythrocytes it localizes to punctate membranous structures external to the parasite (intra-erythrocytic P. berghei-induced structures, IBIS), and its deletion mildly impairs intra-erythrocytic growth in vivo, implicating these structures in rapid parasite expansion (PMID:22329949). In intrahepatocytic parasites IBIS1 labels the parasitophorous vacuole membrane and a connected tubovesicular network whose vesicles and tubules extend and contract from the PVM in a microtubule-dependent manner and associate with host late endosomes/lysosomes and the autophagosome marker LC3 (PMID:24423236). IBIS1 serves as a scaffold/component of a multi-protein complex, co-precipitating and co-localizing with the tryptophan-rich proteins IPIS2 and IPIS3 at IBIS and at the liver-stage PVM (PMID:36126089). Heterologous expression of P. berghei IBIS1 in P. falciparum results in export to Maurer's clefts, indicating evolutionary conservation of these parasite-induced compartments (PMID:25956941).

1. 2012 High

   It was unknown what proteins define the exported membranous structures at the P. berghei/host interface; identifying IBIS1 as an exported PEXEL/HT protker marking these structures established a molecular handle on parasite-induced compartments and linked them to parasite growth.

   Evidence Fluorescent tagging, biochemical fractionation, and targeted gene deletion with in vivo growth phenotyping in P. berghei

   PMID:22329949

   Open questions at the time

   • The molecular function of IBIS1 within these structures was not defined
   • The mechanism linking IBIS to rapid parasite expansion was not established
   • The composition of the IBIS membrane compartment beyond IBIS1 was unknown
2. 2014 High

   Whether IBIS1-marked membranes were static or dynamic and how they interfaced with host organelles was unknown; live imaging, CLEM, and FRAP showed IBIS1 labels a microtubule-dependent, dynamic PVM/tubovesicular network that contacts host late endosomes/lysosomes and recruits LC3, establishing an active parasite-host membrane interface in the liver stage.

   Evidence Fluorescent tagging, live microscopy, CLEM, FRAP, and pharmacological microtubule disruption in intrahepatocytic P. berghei

   PMID:24423236

   Open questions at the time

   • The functional consequence of host endosome/lysosome and LC3 recruitment for the parasite was not resolved
   • Whether microtubule dependence reflects host or parasite cytoskeleton was not fully dissected
   • The molecular activity driving membrane extension remained unknown
3. 2015 Medium

   Whether IBIS-type compartments are P. berghei-specific or evolutionarily conserved was unknown; heterologous expression showed P. berghei IBIS1 traffics to Maurer's clefts in P. falciparum, arguing that IBIS and Maurer's clefts are conserved parasite-induced structures.

   Evidence Heterologous expression of tagged P. berghei IBIS1 in P. falciparum with fluorescence microscopy

   PMID:25956941

   Open questions at the time

   • Functional consequence of Maurer's cleft localization was not directly tested
   • The endogenous P. falciparum homologue relationship was only partially explored
   • Trafficking capability in a heterologous host does not establish native function
4. 2022 Medium

   It was unknown whether IBIS1 acts alone or organizes a complex; immunoprecipitation with IBIS1 as bait and co-localization identified tryptophan-rich interactors IPIS2 and IPIS3, establishing IBIS1 as a scaffold/component of a multi-protein complex at parasite-induced membrane structures.

   Evidence Co-immunoprecipitation with IBIS1 as bait, fluorescence co-localization, and interactor gene deletion in P. berghei

   PMID:36126089

   Open questions at the time

   • Reciprocal co-IP validation and direct binding were not established
   • The molecular activity contributed by IBIS1 to the complex was not defined
   • The stoichiometry and architecture of the complex were not resolved

• The biochemical activity of IBIS1 and the mechanism by which it and its complex remodel the parasite-host membrane interface to promote parasite growth remain unresolved.
• No enzymatic or biochemical activity has been assigned to IBIS1
• No structural model of IBIS1 or its complex exists in the corpus
• The causal chain from IBIS1 membrane structures to the growth phenotype is undefined