PATPL1

PATPL1 (PF3D7_0209100) is a cytoplasmic patatin-like phospholipase that governs sexual-stage progression and transmission of Plasmodium falciparum (PMID:31413195, PMID:31734953). It possesses phospholipase A2 (PLA2) activity in vitro, consistent with its patatin-like domain (PMID:31413195). PATPL1 is dispensable for asexual intraerythrocytic growth, but its conditional deletion reduces the efficiency of gametocyte rounding up, egress, and male gamete exflagellation, and diminishes oocyst formation in Anopheles mosquitoes (PMID:31413195). Mechanistically, PATPL1 acts upstream of the perforin-like protein PfPLP2, and its loss impairs PfPLP2 secretion, linking its phospholipase activity to the egress machinery (PMID:31413195). A separate study instead implicates PATPL1 in gametocyte induction: its loss impairs sexual commitment while overexpression promotes gametocyte formation, correlated with elevated phosphatidylcholine and other phospholipids (consistent with a PLA2 role in phospholipid degradation) and with transcriptional downregulation of the sexual commitment regulator AP2-G (PMID:31734953). The two studies report contradictory conclusions about which stage of sexual development PATPL1 primarily controls.

1. 2019 Medium

   Establishing that PATPL1 is an enzymatically active phospholipase converted a domain-based annotation into a biochemically defined PLA2 activity.

   Evidence In vitro PLA2 activity assay of PATPL1 in P. falciparum

   PMID:31413195

   Open questions at the time

   • Catalytic residues not mutated to confirm the activity derives from the patatin domain
   • In vivo substrate specificity not defined
   • Activity assayed in a single study
2. 2019 High

   Conditional deletion defined which stages depend on PATPL1, showing it is dispensable for asexual growth but required for efficient gametocyte rounding up, egress, and exflagellation.

   Evidence DiCre conditional gene deletion with phenotypic assays for rounding up, egress, and exflagellation in P. falciparum

   PMID:31413195

   Open questions at the time

   • Molecular trigger linking PLA2 activity to the rounding-up/egress program not resolved
   • Whether phospholipase activity is required for the phenotype not tested by catalytic-dead complementation
3. 2019 High

   Placing PATPL1 upstream of PfPLP2 secretion provided a mechanistic route by which its loss impairs gamete egress.

   Evidence DiCre conditional deletion combined with assay of PfPLP2 secretion/localization in P. falciparum

   PMID:31413195

   Open questions at the time

   • Whether PATPL1 acts directly on the PfPLP2 secretory pathway or indirectly via membrane lipid remodeling is unknown
   • No physical interaction between PATPL1 and PfPLP2 demonstrated
4. 2019 High

   Mosquito infection experiments extended PATPL1's role from gametogenesis to transmission by showing reduced oocyst formation upon deletion.

   Evidence DiCre conditional deletion followed by Anopheles infection and oocyst counting

   PMID:31413195

   Open questions at the time

   • Whether the oocyst defect is fully attributable to the upstream exflagellation/egress defect not separated
   • No ookinete-stage analysis
5. 2019 Medium

   Localization of tagged PATPL1 to the cytoplasm situated the phospholipase in a soluble compartment during both asexual and sexual blood stages.

   Evidence Fluorescence microscopy of tagged PATPL1 in blood-stage P. falciparum

   PMID:31734953

   Open questions at the time

   • No functional consequence directly tied to the observed localization
   • Dynamic relocalization during gametogenesis not examined
6. 2019 Medium

   A second study assigned PATPL1 a role in gametocyte induction via loss- and gain-of-function, and proposed a lipid-signaling mechanism, directly conflicting with the gametogenesis-stage model.

   Evidence Gene disruption/knockdown, overexpression with gametocyte induction assays, lipidomics, and transcriptional analysis of AP2-G in P. falciparum

   PMID:31734953

   Open questions at the time

   • Contradicts the finding that PATPL1 is required at gametogenesis rather than commitment (idx 1)
   • Causal link from elevated phosphatidylcholine to AP2-G suppression remains a hypothesis
   • Single lab, single method for the lipidomic and transcriptional readouts

• It remains unresolved whether PATPL1 primarily controls gametocyte commitment (via phospholipid/AP2-G signaling) or gametogenesis (via PfPLP2 secretion), and whether its catalytic PLA2 activity is required for either.
• No catalytic-dead complementation to test whether phenotypes depend on PLA2 activity
• The two published models make contradictory stage assignments and have not been reconciled
• No structural model or in vivo substrate identification