Phospholipase A2: Potential roles in native membrane fusion

Dabral, Deepti; Coorssen, Jens R.

doi:10.1016/j.biocel.2017.01.011

Cited by 7 publications

(14 citation statements)

References 45 publications

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“…PLA2s have also been im-plicated in regulating vesicle docking by mediating the synthesis and release of fatty acids such as arachidonic acid (21,22). Arachidonic acid can enable vesicular docking by promoting SNARE (soluble NSF attachment protein [SNAP] receptor) complex formation between membranes (23)(24)(25). These mechanisms may be responsible for the role of PfPATPL1 in secretion of PfPLP2-containing vesicles following gametocyte activation.…”

Section: Discussionmentioning

confidence: 99%

Role of a patatin-like phospholipase inPlasmodium falciparumgametogenesis and malaria transmission

Singh

Alaganan

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Transmission of Plasmodium falciparum involves a complex process that starts with the ingestion of gametocytes by female Anopheles mosquitoes during a blood meal. Activation of gametocytes in the mosquito midgut triggers “rounding up” followed by egress of both male and female gametes. Egress requires secretion of a perforin-like protein, PfPLP2, from intracellular vesicles to the periphery, which leads to destabilization of peripheral membranes. Male gametes also develop flagella, which assist in binding female gametes for fertilization. This process of gametogenesis, which is key to malaria transmission, involves extensive membrane remodeling as well as vesicular discharge. Phospholipase A2 enzymes (PLA2) are known to mediate membrane remodeling and vesicle secretion in diverse organisms. Here, we show that a P. falciparum patatin-like phospholipase (PfPATPL1) with PLA2 activity plays a key role in gametogenesis. Conditional deletion of the gene encoding PfPATPL1 does not affect P. falciparum blood stage growth or gametocyte development but reduces efficiency of rounding up, egress, and exflagellation of gametocytes following activation. Interestingly, deletion of the PfPATPL1 gene inhibits secretion of PfPLP2, reducing the efficiency of gamete egress. Deletion of PfPATPL1 also reduces the efficiency of oocyst formation in mosquitoes. These studies demonstrate that PfPATPL1 plays a role in gametogenesis, thereby identifying PLA2 phospholipases such as PfPATPL1 as potential targets for the development of drugs to block malaria transmission.

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Section: Discussionmentioning

confidence: 99%

Role of a patatin-like phospholipase inPlasmodium falciparumgametogenesis and malaria transmission

Singh

Alaganan

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…The proposed ‘housekeeping’ function of iPLA 2 is to generate lyso-phospholipid acceptors for the incorporation of FFA into membrane phospholipids [34,35,64,82]. Upon iPLA 2 inhibition, lyso-phospholipid acceptor levels decrease, consequently leading to an increase in FFA concentration [29,64]. Under such a condition, the bulk of FFA is incorporated in the de novo metabolites TAG, DAG and MAG (Figure S1A,B) [64].…”

Section: Discussionmentioning

confidence: 99%

“…Overall, the data suggested the presence of more than one catalytically active form of PLA 2 on CSC, some of which may be strategically localized to maintain the docked and release-ready state of CV on the PM [29]. Blocking PLA 2 activities using well characterized iPLA 2 inhibitors (BEL [78] and FKGK-11 [35,67]) and an sPLA 2 inhibitor (LY311727 [68]) caused significant inhibition of CSC fusion suggesting that even fully docked and fusion-ready CV are sensitive to changes in local PLA 2 activity (Figure 1B and Figure 2).…”

Section: Discussionmentioning

confidence: 99%

“…Once secreted, their Ca 2+ requirement for catalysis is in the low millimolar (mM) range with no strict fatty acid selectivity, although mostly target phosphatidyl-ethanolamine, -glycerol, -inositol and -serine (PE, PG, PI and PS) [26,27]. Although these enzymes are generally thought to be active only when released into the extracellular space, the possibility of basal sPLA 2 activity in the vesicle lumen has been suggested [17,28,29]. In transfected CHO-K1 and HEK293 cells that lack regulated secretory vesicles, expressed sPLA 2 was localized to the golgi and related intracellular vesicles and released ARA, indicating basal activity [28].…”

Section: Introductionmentioning

confidence: 99%

“…The mammalian forms include iPLA 2 β, iPLA 2 γ, iPLA 2 δ, iPLA 2 ε, iPLA 2 ζ and iPLA 2 η with molecular weights ranging from 27 to 146 kDa. A well-established function of iPLA 2 β is membrane phospholipid remodelling via Lands cycle to maintain membrane integrity [29,34,35]. cPLA 2 are cytosolic proteins of molecular weights ranging from 61-114 kDa and require micromolar [Ca 2+ ] free for association with membrane phospholipids via their N-terminal C2 domain [25,26].…”

Section: Introductionmentioning

confidence: 99%

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Combined Targeted Omic and Functional Assays Identify Phospholipases A2 that Regulate Docking/Priming in Calcium-Triggered Exocytosis

Dabral

Coorssen

2019

Cells

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The fundamental molecular mechanism underlying the membrane merger steps of regulated exocytosis is highly conserved across cell types. Although involvement of Phospholipase A2 (PLA2) in regulated exocytosis has long been suggested, its function or that of its metabolites—a lyso-phospholipid and a free fatty acid—remain somewhat speculative. Here, using a combined bioinformatics and top-down discovery proteomics approach, coupled with lipidomic analyses, PLA2 were found to be associated with release-ready cortical secretory vesicles (CV) that possess the minimal molecular machinery for docking, Ca2+ sensing and membrane fusion. Tightly coupling the molecular analyses with well-established quantitative fusion assays, we show for the first time that inhibition of a CV surface calcium independent intracellular PLA2 and a luminal secretory PLA2 significantly reduce docking/priming in the late steps of regulated exocytosis, indicating key regulatory roles in the critical step(s) preceding membrane merger.

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Arachidonic acid and lysophosphatidylcholine inhibit multiple late steps of regulated exocytosis

Dabral

Coorssen

2019

Biochemical and Biophysical Research Communications

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Phospholipase A2: Potential roles in native membrane fusion

Cited by 7 publications

References 45 publications

Role of a patatin-like phospholipase inPlasmodium falciparumgametogenesis and malaria transmission

Role of a patatin-like phospholipase inPlasmodium falciparumgametogenesis and malaria transmission

Combined Targeted Omic and Functional Assays Identify Phospholipases A2 that Regulate Docking/Priming in Calcium-Triggered Exocytosis

Arachidonic acid and lysophosphatidylcholine inhibit multiple late steps of regulated exocytosis

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