DHHC10

DHHC10 (PF3D7_1027900) is a putative DHHC-CRD palmitoyl-S-acyltransferase that functions in the sexual and mosquito-transmission stages of the malaria parasite rather than in asexual blood-stage growth (PMID:27303037, PMID:23638681). In Plasmodium berghei, its mRNA is translationally repressed in female gametocytes and translationally activated during ookinete formation, after which the protein localizes to the crystalloid organelle and is required for crystalloid biogenesis, for correct targeting of the crystalloid-resident cargo protein LAP2, and for parasite transmission to mosquitoes (PMID:27303037). Consistent with this stage-specific role, DHHC10 knockout is viable and dispensable for asexual blood-stage growth in P. berghei, unlike several other DHHC family members (PMID:23638681). In P. falciparum, the DHHC10 transcript is likewise present among translationally repressed maternal mRNAs in female gametocytes with no detectable protein, indicating conservation of its storage-for-post-fertilization regulatory pattern (PMID:27298255). Beyond its localization and the LAP2 mistargeting phenotype, the direct palmitoylation substrates and enzymatic mechanism of DHHC10 have not been characterized in the available corpus.

1. 2013 Medium

   Whether DHHC10 is required for parasite survival was unknown; establishing that a viable knockout could be generated defined it as dispensable for asexual proliferation and pointed toward a stage-restricted role.

   Evidence Genome-wide reverse genetic knockout screen of Plasmodium and Toxoplasma DHHC-CRD palmitoyltransferases with localization analysis in P. berghei

   PMID:23638681

   Open questions at the time

   • Does not identify the stage or process in which DHHC10 is required
   • No substrate or enzymatic activity assigned
   • Mechanistic details secondary to the broader family screen
2. 2016 High

   The functional role of DHHC10 was resolved by showing it is translationally repressed in female gametocytes, activated during ookinete formation, localizes to the crystalloid organelle, and is required for crystalloid biogenesis, LAP2 targeting, and mosquito transmission.

   Evidence Reverse genetics (null mutant), fluorescence localization, and translational repression analysis in P. berghei

   PMID:27303037

   Open questions at the time

   • Direct palmitoylation substrates of DHHC10 not identified
   • Whether LAP2 mistargeting is a direct or indirect consequence unresolved
   • Enzymatic mechanism and acyl-CoA specificity not tested
3. 2016 Medium

   Whether the translational-repression regulation extends to human-infective parasites was addressed by detecting DHHC10 mRNA but not protein among stored maternal transcripts in P. falciparum female gametocytes.

   Evidence Integrated transcriptomic and proteomic comparison of male and female P. falciparum gametocytes

   PMID:27298255

   Open questions at the time

   • Indirect inference of translational repression from mRNA/protein discordance
   • Post-fertilization localization and function not tested in P. falciparum
   • No functional knockout in P. falciparum

• The direct palmitoylation substrates of DHHC10 and the biochemical basis by which it drives crystalloid biogenesis and LAP2 targeting remain unidentified.
• No demonstrated acyltransferase activity or palmitoylated substrate for DHHC10
• Whether LAP2 or crystalloid cargo are direct substrates is untested
• No structural or catalytic-mutant analysis