gms | German Medical Science

The human malaria parasite Plasmodium falciparum possesses a functional proteasome, which plays an essential role for the different parasite life-cycle stages, including the blood and gametocyte stages of the parasite. Genome annotation studies revealed the presence of genes encoding for all of the known proteasome subunits, including the lid and base proteins of the regulatory particle. In this context a plasmodial homolog of the metalloprotease Rpn11 was identified, which is predicted to be involved in substrate deubiquitination prior to proteasomal degradation. Yeast Rpn11 contains a highly conserved Jab1/MPN domain-associated metalloisopeptidase (JAMM) motif-EX(n)HXHX(10)D, and mutation of the predicted active-site histidines to alanine (rpn11AXA) was lethal and proteasomes failed to either deubiquitinate or degrade ubiquitinated substrate. Recent studies further showed that yeast Rpn11 is forming a dimer with Rpn8 through an interface between the MPN domains of the two proteins, which is important for the enzymatic activity of Rpn11. In P. falciparum, protein interaction studies indicated that Rpn11 is associated with the proteasomal lid component Rpn6 and that it further interacts with MSP1, Pf39 and the exported protein PF3D7_0730800.1. Preliminary results from our lab, using Rpn11-specific mouse antisera, showed that Rpn11 of P. falciparum is expressed in the parasite blood and gametocyte stages. Surprisingly, Rpn11 does not co-localize with the parasite proteasome, but is rather exported into the erythrocyte cytoplasm during blood stage replication.

We currently aim to investigate expression and activity of Rpn11 as well as its potential interaction with other lid subunits or exported proteins of P. falciparum.