RPN11

PF3D7_1368100 (RPN11) is a putative 19S proteasome lid subunit in Plasmodium falciparum whose characterization in the available corpus rests on two indirect lines of evidence. Bioinformatic analysis places RPN11 among only three P. falciparum proteins carrying an IPR000555 JAB1/MPN/MOV34 metalloenzyme domain, and unlike its paralogs PfRpn8 and PfeIF3f — which bear catalytically inactive MPN- domains — RPN11 retains the essential catalytic residues of an active MPN+ (JAMM) metalloprotease domain predicted to confer deubiquitinating activity (PMID:31658303). In artemisinin-resistant parasites (Dd2R539T), RPN11 protein levels are translationally upregulated after a dihydroartemisinin pulse while its transcript level falls, indicating post-transcriptional control, and the gene is classified as essential (PMID:38632343). Beyond these domain-level and observational findings, no direct enzymatic, mutagenic, or structural experiments on PfRPN11 itself have been reported in the available corpus.

1. 2019 Low

   To ask whether P. falciparum encodes a proteasomal deubiquitinase, domain analysis established that RPN11 uniquely retains an active MPN+ (JAMM) metalloprotease domain, distinguishing it from catalytically dead paralogs.

   Evidence Bioinformatic IPR000555 domain search and catalytic-residue inspection in the context of a deNeddylase chemical screen

   PMID:31658303

   Open questions at the time

   • No direct enzymatic assay or mutagenesis performed on PfRPN11 to confirm deubiquitinating activity
   • No structural model of the domain in the assembled proteasome
   • Predicted substrate specificity not tested
2. 2024 Low

   To probe how the proteasome contributes to artemisinin resistance, proteomic/transcriptomic profiling showed RPN11 protein is translationally upregulated after DHA pulse in resistant parasites while its transcript falls, pointing to post-transcriptional regulation and essentiality.

   Evidence Integrated mass spectrometry and transcriptomics of synchronized ART-sensitive vs. resistant Dd2R539T parasites before/after DHA pulse, with codon-usage analysis

   PMID:38632343

   Open questions at the time

   • Observational correlation only; no functional assay linking RPN11 levels to resistance
   • Mechanism of translational upregulation not defined
   • Essentiality claim not supported by a direct genetic knockout in this study

• Whether PfRPN11 actually possesses deubiquitinating activity, how it assembles into and functions within the 19S proteasome, and whether its regulation causally contributes to artemisinin resistance remain undetermined.
• No reconstitution or in vitro assay of PfRPN11 metalloprotease/DUB activity
• No structure or proteasome-assembly data for PfRPN11
• No causal link between RPN11 upregulation and ART resistance