RRP6

PF3D7_1449700 (RRP6) is a catalytically active ribonuclease of the Plasmodium falciparum RNA exosome-like complex that couples ncRNA turnover to heterochromatic gene silencing (PMID:29664138, PMID:32487761). Recombinant RRP6 degrades single-stranded RNA in vitro, establishing it as an enzymatically active exonuclease, and localizes to the cytoplasm by immunofluorescence (PMID:29664138). In the control of variant gene expression, RRP6 mediates decay of nascent RUF6 ncRNA transcripts: knockdown stabilizes and accumulates RUF6 ncRNA, which remodels local chromatin at adjacent var loci and interacts with distal heterochromatic regions, globally derepressing heterochromatic gene families and the sexual commitment regulator ap2-g (PMID:32487761). Beyond its ssRNA exonuclease activity and this RUF6-dependent silencing role, no further mechanistic detail (e.g. catalytic-residue mapping, structural model, or defined complex composition) has been characterized for RRP6 in the available corpus.

1. 2018 Medium

   Whether PF3D7_1449700 is an active nuclease or merely a structural subunit of the exosome-like complex was unresolved; demonstrating intrinsic catalytic activity established it as an enzymatically functional component.

   Evidence In vitro RNA degradation assay with recombinant PfRrp6 protein plus indirect immunofluorescence for localization

   PMID:29664138

   Open questions at the time

   • No catalytic-residue mutagenesis or structural validation of the active site
   • Single lab, single study
   • Cytoplasmic localization does not by itself explain a nuclear silencing role
2. 2020 High

   The biological substrate and function of RRP6 nuclease activity in vivo were unknown; loss-of-function showed it degrades RUF6 ncRNA to enforce heterochromatic gene silencing, linking RNA decay to epigenetic control of virulence and sexual commitment genes.

   Evidence Genetic knockdown in P. falciparum with ChIRP-seq, chromatin profiling, and transcriptomics

   PMID:32487761

   Open questions at the time

   • Does not establish whether RRP6 acts directly on RUF6 in the nucleus or via the full exosome complex
   • Composition of the P. falciparum exosome-like complex containing RRP6 not defined here
   • Reconciliation of cytoplasmic localization [#0] with a nuclear ncRNA-decay function not resolved

• Whether RRP6's ssRNA exonuclease activity is directly responsible for RUF6 ncRNA turnover in vivo, and the identity of its exosome partner subunits, remain open.
• No catalytic-dead rescue linking enzymatic activity to the silencing phenotype
• No defined subunit composition of the RRP6-containing exosome-like complex
• No structural model