|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Blood, 15 October 2003, Vol. 102, No. 8, pp. 2714-2715.
Another way for sPLA2 to meet with cellsPhospholipase A2 (PLA2) hydrolyzes membrane phospholipids to produce free fatty acids and lysophospholipids, thereby providing precursors for the biosynthesis of a variety of lipid mediators. Secretory PLA2 (sPLA2) comprises a subfamily of Ca2+-dependent, low–molecular weight enzymes with a conserved Ca2+ binding loop and catalytic His-Asp dyad. To date, 10 sPLA2 isozymes (IB, IIA, IIC, IID, IIE, IIF, III, V, X, and XII), which exhibit tissue-specific expression, have been identified in mammals.Recent progress in this research area has established 3 distinct pathways whereby sPLA2s interact with mammalian cell membranes.1 First, the ability of sPLA2s to act on cells depends on their interfacial binding to phosphatidylcholine (PC) that is enriched in the outer leaflet of the plasma membrane. The 2 enzymes with high–PC-binding property, sPLA2-V and -X, can use this pathway.2 Second, several cationic sPLA2s such as sPLA2-IIA, -IID, and -V bind to cell membranes through association with anionic heparan sulfate proteoglycan (HSPG), such as glypican. The sPLA2s captured by heparan sulfate chains of HSPG are often sorted into caveolae/rafts upon cell activation and then internalized into vesicular and perinuclear membrane compartments where they exert membrane-hydrolytic action.3 Third, several sPLA2s, such as sPLA2-IB and -X, bind to the M-type sPLA2 receptor, which leads to cell activation through the receptor-coupled signaling process or to inactivation of sPLA2s, depending on experimental systems.4 Beyond these aspects, however, the physiologic functions of individual sPLA2s are still subject to debate. sPLA2-IIA is a prototypic sPLA2 found abundantly in the inflammatory exudates and is considered to play an important role in the process of inflammation and host defense. Several studies have demonstrated that the enzymatic action of sPLA2-IIA on mammalian cells is facilitated during apoptosis probably because phosphatidylserine, a preferred substrate for this enzyme, is exposed on the apoptotic cell membrane.5 In this issue, Boilard and colleagues (page 2901) have provided another explanation for increased association of sPLA2-IIA with apoptotic cells. They found that there are 2 distinct binding sites for sPLA2-IIA on human T cells after treatment with anti-Fas antibody, one being low–molecular weight HSPG and the other being a 57-kDa uncharacterized protein. By combined analyses of coimmunoprecipitation and matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry, they identified this 57-kDa protein as vimentin, a cytoskeletal protein often found as an autoantigen in the sera from patients with autoimmune diseases. They showed that the residues near or at the active site of sPLA2-IIA interact with the rod domain of vimentin exposed on the external surface of apoptotic T cells. Furthermore, the vimentin-bound sPLA2-IIA exhibits enhanced enzymatic activity toward exogenous phospholipids. Thus, they proposed that the interaction of sPLA2-IIA with vimentin has an anchoring function that enables its enzymatic action toward cellular membranes. In this context, the study by Boilard and colleagues has represented a novel way for sPLA2 to interact with mammalian cells. However, several issues should be addressed in order to evaluate the biologic impacts of the sPLA2-IIA–vimentin interaction on human pathophysiology. It remains unresolved whether the sPLA2-IIA–vimentin interaction can indeed facilitate the hydrolysis of apoptotic cellular membranes. The interaction of sPLA2 with vimentin in conjunction with HSPG may play a role in the compartmentalization of this enzyme in particular membrane microdomains in which the enzyme functions, as has been reported for the interaction between sPLA2 and HSPG. However, why does it have to take place in apoptotic cells? More important, it is critical to determine whether the event can occur in vivo. It also would be interesting to know whether other sPLA2 isozymes can use the same machinery to interact with apoptotic cells. Clarifying these issues will contribute to our understanding of the physiologic function of sPLA2 in the immune response.
References
  CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2003 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
