Another way for sPLA₂ to meet with cells

Phospholipase 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.