Essential Ca2+-independent Role of the Group IVA Cytosolic Phospholipase A2 C2 Domain for Interfacial Activity

Six, David A.; Dennis, Edward A.

doi:10.1074/jbc.m301386200

Cited by 74 publications

(84 citation statements)

References 68 publications

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“…It is now clear that cPLA 2 ␣ activity is essential for the generation of LD after TAG present in the endoplasmic reticulum (7,10); however, we have consistently found no enzyme translocation to the nuclear envelope and nearby membranes in response to FBS (10). Bearing in mind that the D43N mutation does not suppress interfacial activity of the C2 domain (34), in our experimental model the enzyme could interact with the diffuse endoplasmic reticulum membrane system and/or nascent LD. This would probably escape detection in our studies, which were carried out within minutes following FBS stimulation (10).…”

Section: Discussionmentioning

confidence: 55%

“…Moreover, the single mutation D43N in the C2 domain of the enzyme, which abrogates its Ca 2ϩ binding capacity, does not affect activity in response to FBS. Several reports have established the dispensability of Ca 2ϩ rises in terms of full enzyme activation in vivo (13, 16 -19) while putting forward the requirement of the signaling lipids PtdIns-4,5-P 2 (17,20,21,34) and Cer-1-P to allow interaction with membranes (22)(23)(24)(25). The D43N mutation in cPLA 2 ␣ renders the enzyme refractory to physiological Ca 2ϩ concentrations (31), but it is fully active on PtdIns-4,5-P 2 -containing micelles (34).…”

Section: Discussionmentioning

confidence: 99%

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JNK and Ceramide Kinase Govern the Biogenesis of Lipid Droplets through Activation of Group IVA Phospholipase A2

Gubern

Barceló-Torns

Barneda

et al. 2009

Journal of Biological Chemistry

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The biogenesis of lipid droplets (LD) induced by serum depends on group IVA phospholipase A 2 (cPLA 2 ␣). This work dissects the pathway leading to cPLA 2 ␣ activation and LD biogenesis. Both processes were Ca 2؉ -independent, as they took place after pharmacological blockade of Ca 2؉ transients elicited by serum or chelation with 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid tetrakis(acetoxymethyl ester). The single mutation D43N in cPLA 2 ␣, which abrogates its Ca 2؉ binding capacity and translocation to membranes, did not affect enzyme activation and formation of LD. In contrast, the mutation S505A did not affect membrane relocation of the enzyme in response to Ca 2؉ but prevented its phosphorylation, activation, and the appearance of LD. Expression of specific activators of different mitogen-activated protein kinases showed that phosphorylation of cPLA 2 ␣ at Ser-505 is due to JNK. This was confirmed by pharmacological inhibition and expression of a dominant-negative form of the upstream activator MEKK1. LD biogenesis was accompanied by increased synthesis of ceramide 1-phosphate. Overexpression of its synthesizing enzyme ceramide kinase increased phosphorylation of cPLA 2 ␣ at Ser-505 and formation of LD, and its down-regulation blocked the phosphorylation of cPLA 2 ␣ and LD biogenesis. These results demonstrate that LD biogenesis induced by serum is regulated by JNK and ceramide kinase.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

JNK and Ceramide Kinase Govern the Biogenesis of Lipid Droplets through Activation of Group IVA Phospholipase A2

Gubern

Barceló-Torns

Barneda

et al. 2009

Journal of Biological Chemistry

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“…We have previously reported that phosphatidylinositol 4,5-bisphosphate activates cPLA 2 ␣ and increases its affinity for calcium (66). Phosphatidylinositol 4,5-bisphosphate also promotes binding of cPLA 2 ␣ to phospholipid vesicles and a role for the catalytic domain has been suggested (67,68). It is therefore interesting to speculate that formation of polyphosphoinositides at the phagosome membrane and in ruffles may play a role in localization of cPLA 2 ␣ at these sites.…”

Section: Discussionmentioning

confidence: 98%

Cytosolic Phospholipase A2 Translocates to Forming Phagosomes during Phagocytosis of Zymosan in Macrophages

Girotti

Evans

Burke

et al. 2004

Journal of Biological Chemistry

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Resident tissue macrophages mediate early innate immune responses to microbial infection. Cytosolic phospholipase A 2 ␣ (cPLA 2 ␣) is activated in macrophages during phagocytosis of non-opsonized yeast (zymosan) triggering arachidonic acid release and eicosanoid production. cPLA 2 ␣ translocates from cytosol to membrane in response to intracellular calcium concentration ([Ca 2؉ ] i ) increases. Enhanced green fluorescent protein (EGFP)-cPLA 2 ␣ translocated to forming phagosomes, surrounding the zymosan particle by 5 min and completely overlapping with early endosome (Rab5) and plasma membrane (F4/80) markers but only partially overlapping with resident endoplasmic reticulum proteins (GRP78 and cyclooxygenase 2). EGFP-cPLA 2 ␣ also localized to membrane ruffles during phagocytosis. Zymosan induced an initial high amplitude calcium transient that preceded particle uptake followed by a low amplitude sustained calcium increase. Both phases were required for optimal phagocytosis. Extracellular calcium chelation prevented only the sustained phase but allowed a limited number of phagocytic events, which were accompanied by translocation of cPLA 2 ␣ to the phagosome although [Ca 2؉ ] i remained at resting levels. The results demonstrate that cPLA 2 ␣ targets the phagosome membrane, which may serve as a source of arachidonic acid for eicosanoid production.

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“…2B). In this setting, cPLA 2 is translocated to the membrane in a Ca 2+ -independent fashion by increased membrane affinity and enhanced specific activity that has been linked to generation of PIP 2 and conformational changes (5,(31)(32)(33), as well as generation of C1P (34), ceramide (35), and diacylglycerol (36). Additionally, sPLA 2 is reported to significantly contribute to prostaglandin production during late-phase activation, but not during 10-min calcium ionophore-induced metabolism (37).…”

Section: Discussionmentioning

confidence: 99%

Omega-3 fatty acids cause dramatic changes in TLR4 and purinergic eicosanoid signaling

Norris

Dennis²

2012

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

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162

129

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Dietary fish oil omega‐3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), elicit cardioprotective and anti‐inflammatory effects through unresolved mechanisms. EPA and DHA may reduce arachidonic acid (AA) metabolism and pro‐inflammatory effects by competition and inhibition at multiple levels. Here, we report the effects of AA, EPA, and DHA supplementation on membrane incorporation, phospholipase A2 release, and eicosanoid production in RAW264.7 macrophages. Each PUFA supplemented increased by similar amounts in membrane phospholipids, while half of the increased AA and EPA were elongated to adrenic acid (AdA) and docosapentaenoic acid (DPA), respectively; and were subsequently released by PLA2 at levels comparable to AA. TLR‐4 stimulated COX‐2 AA production did not increase with AA supplementation and was inhibited by 20% and 50% after EPA and DHA supplementation, respectively. ATP stimulated COX‐1 AA production was inhibited to a greater extent by EPA and DHA; 5‐LOX AA metabolites increased 2‐fold with EPA and DHA supplementation, and 5‐LOX metabolized EPA and DHA to a greater extent than COX‐1/COX‐2. Altogether, AA, EPA and DHA supplementation decreased TLR‐4 stimulated AA COX‐2 prostanoid metabolism; increased the purinergic stimulated AA 5‐LOX/COX‐1 ratio; and significantly increased elongated PUFA levels that may be converted to novel mediators.

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Essential Ca2+-independent Role of the Group IVA Cytosolic Phospholipase A2 C2 Domain for Interfacial Activity

Cited by 74 publications

References 68 publications

JNK and Ceramide Kinase Govern the Biogenesis of Lipid Droplets through Activation of Group IVA Phospholipase A2

JNK and Ceramide Kinase Govern the Biogenesis of Lipid Droplets through Activation of Group IVA Phospholipase A2

Cytosolic Phospholipase A2 Translocates to Forming Phagosomes during Phagocytosis of Zymosan in Macrophages

Omega-3 fatty acids cause dramatic changes in TLR4 and purinergic eicosanoid signaling

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