IPIS2

PBANKA_0524300 (IPIS2) is a tryptophan-rich domain-containing protein of Plasmodium berghei that contributes to remodeling of the host erythrocyte and to establishing sequestration of infected cells during blood-stage infection (PMID:36126089). It is a component of the intraerythrocytic P. berghei-induced membrane structures (IBIS), where it physically associates with the signature IBIS protein IBIS1 and localizes to these structures in infected red blood cells, while also co-localizing with IBIS1 at the parasitophorous vacuole membrane in liver-stage parasites (PMID:36126089). Functionally, IPIS2 is required for efficient blood-stage growth: its deletion impairs the ability of schizont-infected erythrocytes to bind the host receptor CD36, so that infected cells fail to sequester out of the circulation (PMID:36126089). Beyond its membership in the IBIS complex and its role in CD36-mediated sequestration, no further mechanistic detail — including the molecular basis by which IPIS2 promotes CD36 binding — has been characterized in the available corpus.

1. 2022 Medium

   To place an uncharacterized tryptophan-rich protein into a functional context, IPIS2 was shown to be a physical component of the IBIS complex, establishing it as part of the host-cell-remodeling machinery rather than an isolated protein.

   Evidence Co-immunoprecipitation with IBIS1 followed by mass spectrometry in infected erythrocytes

   PMID:36126089

   Open questions at the time

   • Direct versus indirect interaction with IBIS1 within the complex is not resolved
   • Full composition and stoichiometry of the IBIS complex containing IPIS2 not defined
   • No structural information on how IPIS2 associates with IBIS
2. 2022 Medium

   To determine where IPIS2 acts, its subcellular distribution was mapped, showing it occupies IBIS in blood-stage infected erythrocytes and the parasitophorous vacuole membrane in liver stage, indicating stage-specific deployment at host-parasite interfaces.

   Evidence Immunofluorescence and live imaging across blood and liver stages

   PMID:36126089

   Open questions at the time

   • Mechanism of trafficking/export of IPIS2 to these compartments unknown
   • Topology and membrane orientation of IPIS2 not established
3. 2022 High

   To test whether IPIS2 has a required function, gene deletion demonstrated it is needed for efficient blood-stage growth and specifically for CD36 binding, linking the IBIS-localized protein to the sequestration of infected erythrocytes.

   Evidence Gene deletion with CD36-binding assay and in vivo sequestration readout in P. berghei

   PMID:36126089

   Open questions at the time

   • Molecular mechanism connecting IPIS2 to CD36 ligand presentation on the erythrocyte surface unknown
   • Whether IPIS2 acts directly or via trafficking/organizing another surface ligand not determined
   • Contribution of the liver-stage PVM localization to phenotype not addressed

• How IPIS2 mechanistically enables CD36 binding — whether by exporting or organizing a surface adhesin, or by structuring the IBIS/host-membrane interface — remains unresolved.
• No identified surface adhesin downstream of IPIS2
• No structure or domain-function dissection of the tryptophan-rich region
• No biochemical demonstration of direct CD36 contact