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  • Related with the studies by Zizza

    2020-02-22

    Related with the studies by Zizza et al. described above [66], work by Ward et al. [68] suggested that the C2 domain of cPLA2α, which binds to zwitterionic membranes with high affinity in a Ca2+-dependent manner, has a high membrane remodeling activity, producing dramatic changes in membrane curvature consistent with the role of cPLA2α in the formation of the phagosome. Of note, cPLA2α has long been recognized to regulate the formation of cytoplasmic lipid droplets under different conditions [[69], [70], [71], [72]], by mechanisms likely implicating regulation of positive membrane curvature that is necessary for the nascent organelle to emerge from the endoplasmic reticulum [51]. Most recently, it has been described that cPLA2α activity contributes to the phagosomal escape of Mycobacterium tuberculosis [73,74]. The enzyme appears to facilitate translocation of the microbe from the endosomal to the cytosolic compartment of human THP-1 macrophage-like cells, allowing survival of the microorganism inside the cells. In addition, it was shown that prostaglandin E2 helps to eliminate M. tuberculosis by increasing the apoptosis of infected macrophages. Apoptotic bodies are then captured by dendritic cells that mediate cross-presentation of M. tuberculosis antigens to CD8+T cells to initiate adaptive responses [73,75]. Interestingly, lipoxin A4 increases necrotic processes in infected macrophages, which helps bacteria to evade adaptive immunity [75]. Work by Slatter et al. [76] has unveiled a new biological function of cPLA2α in metabolism, as a regulator of energy production by mitochondria. It was shown that, in thrombin-activated platelets, which produce large amounts of ATP via β-oxidation, cPLA2α activation promotes fatty Nucleozin release and the subsequent β-oxidation of both eicosanoids and fatty acids. The rate of β-oxidation of eicosanoids is balanced with the rate of its generation, limited by cPLA2α, thus forming a positive feedback loop that serves to provide energy, dampen negative effects of excess of eicosanoids or the requirement of ATP as a kinase substrate [76]. Another interesting metabolic role for cPLA2α was described in work by Peña et al. [77], where the enzyme was identified as an early key factor for adipocyte differentiation in vitro. Further, animals deficient in cPLA2α that were subjected to a high fat diet show a reduced capacity to increase body weight and fat mass, highlighting the important role of cPLA2α in regulating adipose tissue enlargement.
    iPLA2-VIA, also often abbreviated as iPLA2β, is perhaps one of the PLA2 enzymes for which more functions have recently been proposed. The enzyme was first found to participate in the regulation of lysophospholipid levels within the Lands\' cycle [[78], [79], [80]]. Later work demonstrated that iPLA2-VIA is a multifaceted enzyme with multiple roles in cell physiology and pathophysiology [35,[81], [82], [83], [84]], being of special relevance in regulating intracellular signaling leading to insulin secretion [35], and phospholipid hydrolysis reactions during apoptosis [[85], [86], [87], [88]]. Regarding eicosanoid production, iPLA2-VIA appears, in general terms, not to play a major role in mediating this response in innate immunity and inflammation, as evidenced by the large number of studies highlighting the lack of effect of selective inhibition of the enzyme in stimulus-induced AA release in multiple immune cells [45,48,57,[89], [90], [91], [92], [93], [94], [95], [96], [97]]. Rather, the involvement of iPLA2-VIA in the eicosanoid response appears to be restricted to specific conditions which depend on cell type, stimulus or lipid mediator to be formed [58,[98], [99], [100], [101], [102], [103], [104], [105], [106]]. In some of the latter studies, a certain preference of iPLA2-VIA for cleaving AA-containing ether phospholipids was noted [105,106]. More recent work has demonstrated that iPLA2-VIA participates in fatty acid remodeling reactions aimed at removing oxidized fatty acyl chains within cardiolipin molecular species [107]. This process, which can be regarded as a special case of the originally described phospholipid remodeling function of iPLA2-VIA, and also agrees with previous observations that oxidation of membranes accelerates iPLA2VIA-catalyzed fatty acid release [28,108], yields monolysocardiolipins that can be esterified back by new non-oxidized fatty acid. The reparation of oxidized phospholipids confers protection of β-cells against external injury [107]. It is interesting to note in this regard that the closely related enzyme iPLA2-VIB (iPLA2γ) has also been shown to play a major role in mediating the release of oxidized acyl chains from oxidized cardiolipins, leading to the production of second messengers and the removal of toxic products derived from oxidative stress in mouse myocardium [109].