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La phospholipase A2 sécrétée de groupe X : Maturation protéolytique et rôles fonctionnels

Abstract : The superfamily of phospholipase A2 currently consists of at least eleven secreted phospholipases A2 (sPLA2s) and twelve intracellular phospholipases A2. These proteins catalyze the hydrolysis of phospholipids at the sn-2 position, releasing free fatty acids and lysophospholipids. Furthermore, phospholipase A2 controls the production of a variety of lipid mediators which are important for multiple cellular functions in various physiological or physiopathological contexts such as inflammatory diseases and cancer. Group X sPLA2 was cloned in 1997 and have peculiar molecular properties. sPLA2-X has the most potent hydrolyzing activity toward phosphatidylcholine and is involved in arachidonic acid (AA) release. sPLA2-X is produced as a proenzyme and has a propeptide of 11 amino acids ending with a dibasic motif. The cellular location and the protease(s) involved in proenzyme conversion have remained unclear. The work of this thesis has allowed to better define the way by which the maturation of group X sPLA2 can be made and how this sPLA2 functions at both physiological and physiopathological levels. Our in vitro studies with recombinant group X proenzymes and transfected cells (HEK293) have shown that a furin-like protease plays a major role in the activation of the enzyme during its secretion. Our work also suggests that the removal of the propeptide can also occur via other proteases and extracellularly as found when using the human colon cancer cell line LOVO as a cellular model. We also studied the maturation of sPLA2-X in mouse tissues in various physiological and physiopathological conditions. Of note, we found that sPLA2-X is stored in large amount and likely in an active form in the acrosome of mouse sperm cells. Finally we discovered a human polymorphism in the propeptide sequence mutating Arg-38 into cysteine and leading to the secretion of an inactive protein that is rapidly degraded after synthesis. In the second part of this thesis, we have shown that the active form of sPLA2-X, but not its proenzyme is able i) to stimulate the proliferation of various mouse colon cell lines, including Colon-26 cancer cells, ii) to protect human red blood cells from infection by P. falciparum, the parasite of malaria, and iii) to control the acrosomal reaction of mouse sperm during capacitation with an important impact on the outcome of in vitro fertilization.
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Submitted on : Friday, July 2, 2010 - 9:54:13 AM
Last modification on : Wednesday, October 14, 2020 - 4:22:43 AM

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Jemel Ikram. La phospholipase A2 sécrétée de groupe X : Maturation protéolytique et rôles fonctionnels. Biochimie [q-bio.BM]. Université Nice Sophia Antipolis, 2009. Français. ⟨tel-00496969⟩

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