Uncovering Common Principles in Protein Export of Malaria Parasites

Abstract

For proliferation, the malaria parasite Plasmodium falciparum needs to modify the infected host cell extensively. To achieve this, the parasite exports proteins containing a Plasmodium export element (PEXEL) into the host cell. Phosphatidylinositol-3-phosphate binding and cleavage of the PEXEL are thought to mediate protein export. We show that these requirements can be bypassed, exposing a second level of export control in the N terminus generated after PEXEL cleavage that is sufficient to distinguish exported from nonexported proteins. Furthermore, this region also corresponds to the export domain of a second group of exported proteins lacking PEXELs (PNEPs), indicating shared export properties among different exported parasite proteins. Concordantly, export of both PNEPs and PEXEL proteins depends on unfolding, revealing translocation as a common step in export. However, translocation of transmembrane proteins occurs at the parasite plasma membrane, one step before translocation of soluble proteins, indicating unexpectedly complex translocation events at the parasite periphery.

Export of virulence proteins by malaria-infected erythrocytes involves remodeling of host actin cytoskeleton

“…[14][15][16] A number of exported proteins do not contain a PEXEL/VTS motif and are thus called PEXEL-negative exported proteins (PNEPs); their transport pathways are unknown. 5,17 Various proteins play a role in trafficking PfEMP1 to the P falciparum-infected RBC membrane and its assembly into knob structures (reviewed in Maier et al protein 1 (MAHRP1), 21 or ring-exported protein 1 (REX1), 22 PfEMP1 cannot be displayed on the RBC membrane. Additionally, a largescale gene-knockout screen in P falciparum identified other proteins required for trafficking and function of PfEMP1.…”

“…The further route of PfEMP1 is largely unknown; it is either trafficked through the erythrocyte cytosol via a vesicular pathway or in a complex where it transiently associates with parasite-induced membranous compartments, named Maurer's clefts (MC). 5 The protein is subsequently translocated onto RBC membranes and anchored in protrusions of the membrane (knobs). 6 Knobs are points of elevation and concentration for PfEMP1 anchoring to host cytoskeleton facilitating binding to receptors on host cells.…”

Maurer's clefts, the enigma of Plasmodium falciparum

“…A transmembrane domain or a signal peptide seems to be essential, most likely for entering the ER and the secretory pathway (41,43,48,106). Unfolding appears to be equally required for PEXELpositive proteins, suggesting similar mode of translocation across the PVM (104,107). Interestingly, processed N termini of PEXELpositive proteins promote the export of a reporter gene, like unprocessed N termini of PEXEL-negative proteins (107).…”

“…Unfolding appears to be equally required for PEXELpositive proteins, suggesting similar mode of translocation across the PVM (104,107). Interestingly, processed N termini of PEXELpositive proteins promote the export of a reporter gene, like unprocessed N termini of PEXEL-negative proteins (107). An open question is whether these proteins are guided through the same or totally distinct translocon.…”

Toxoplasmaexports dense granule proteins beyond the vacuole to the host cell nucleus and rewires the host genome expression

“…In the next step, PEXEL-containing proteins are matured by the Plasmepsin V protease, and the newly exposed N-terminal sequence is likely recognized by the translocation machinery (Boddey and Cowman, 2013b;Marti and Spielmann, 2013). Amino acids within the PEXEL motif after cleavage were shown to be important for export (Gruring et al, 2012;Boddey et al, 2013a;Tarr et al, 2013).…”