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  • Previous studies demonstrated that cPLA translocates to the

    2020-10-16

    Previous studies demonstrated that cPLA2α translocates to the phagosomal membrane during macrophage phagocytosis through mechanisms that, in humans, involve phosphorylation of the enzyme by c-Jun N-terminal kinases and membrane association via the cationic cluster of four lysine residues present at the catalytic domain of the enzyme (Fig. 2) [50,52,[61], [62], [63], [64], [65]]. More recently, it has been shown that the N-terminal C2 domain of cPLA2α is sufficient to support FcR-mediated phagocytosis [66]. Importantly, overexpression of a cPLA2α mutant without a complete catalytic domain, and therefore without enzymatic activity, rescues FcR-mediated phagocytosis in Irinotecan from Pla2g4a−/− mice [66]. Based on these data, the proposal was made that the C2 domain of cPLA2α induces perturbation of the membrane phospholipid packing, potentially generating membrane bending that is necessary for phagosome formation in a manner independent of its enzymatic activity [66]. These studies are important in that they provide the first example of a biological function associated to cPLA2α that does not depend on enzyme activity. It is also worth noting in this regard another recent study implicating cPLA2α in the regulation of the tumor suppressor gene SIRT2 via mechanisms likely independent of the hydrolytic activity of the enzyme [67]. 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 acid 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]].