DIS3

PF3D7_1359300 (DIS3) encodes the catalytic exoribonuclease subunit of the RNA exosome in Plasmodium falciparum, functioning in the turnover of non-coding RNAs during the intraerythrocytic developmental cycle (PMID:29664138, PMID:32079470). The recombinant protein degrades single-stranded RNA in vitro and localizes to the parasite cytoplasm in asexual-stage parasites, where it associates with the RNA exosome core complex (PMID:29664138, PMID:27230797). Together with its cofactor PfMtr4, DIS3 is required for the degradation of nascent non-coding RNAs (ns-ncRNAs), establishing its role in controlling the parasite's non-coding transcriptome (PMID:32079470). Beyond its 3′–5′ ssRNA exonuclease activity, cytoplasmic localization, exosome association, and ns-ncRNA turnover function, no further mechanistic detail—including structural basis, substrate specificity determinants, or catalytic residues—has been characterized in the available corpus.

1. 2018 Medium

   To establish whether PF3D7_1359300 is an active nuclease and where it acts, the recombinant protein was tested biochemically and localized in parasites, defining it as a cytoplasmic ssRNA-degrading exoribonuclease.

   Evidence In vitro ssRNA processing assay with recombinant protein plus indirect immunofluorescence and Western blot in P. falciparum asexual stages

   PMID:29664138

   Open questions at the time

   • No mutagenesis to confirm catalytic residues
   • Substrate specificity beyond generic ssRNA not defined
   • Single lab, no replication
2. 2018 Low

   To determine whether PF3D7_1359300 operates within the exosome machinery rather than in isolation, physical association was tested, placing it in the RNA exosome core complex in the cytoplasm.

   Evidence Co-immunoprecipitation and immunofluorescence in ring-stage P. falciparum parasites

   PMID:27230797

   Open questions at the time

   • Single Co-IP reported secondarily in a review, not independently replicated
   • Stoichiometry and identity of core subunits not resolved
   • No reciprocal pull-down
3. 2020 Medium

   To connect the enzyme to a cellular RNA-regulatory function, inducible knock-down defined its physiological substrates, showing that DIS3 and its cofactor PfMtr4 drive degradation of nascent non-coding RNAs during the intraerythrocytic cycle.

   Evidence Inducible gene knock-down with rRNA-depleted stranded nascent RNA-seq integrated with ATAC-seq and ChIP-seq in P. falciparum

   PMID:32079470

   Open questions at the time

   • Direct enzyme-substrate contacts on ns-ncRNAs not shown
   • Contribution of DIS3 versus PfMtr4 not separated
   • Single lab

• The catalytic mechanism, structural organization within the exosome, and full substrate repertoire of PF3D7_1359300 remain undefined.
• No structure or catalytic-residue mutagenesis
• No comprehensive substrate map beyond ns-ncRNAs
• Role in parasite viability and drug-target potential not established