A yeast PAF acetylhydrolase ortholog suppresses oxidative death

Abstract

Phospholipids containing sn-2 polyunsaturated fatty acyl residues are primary targets of oxidizing radicals, producing proapoptotic and membrane perturbing fragmented phospholipids. The only known phospholipases that specifically select these oxidized and/or short-chained phospholipids as substrates are mammalian group VII phospholipases A2s that were purified and cloned as PAF acetylhydrolases. Platelet-activating factor (PAF) is a short-chained phospholipid, and whether these enzymes actually are PAF hydrolases or evolved as oxidized phospholipid phospholipases is unknown. The fission yeast Schizosaccharomyces pombe, which does not form or use PAF as a signaling molecule, contains an open-reading frame potentially homologous to mammalian group VII phospholipase A2s. We cloned this SPBC106.11c locus and expressed it in distantly related Saccharomyces cerevisiae that lack homologous sequences. The S. pombe locus encoded a functional phospholipase A2, now renamed plg7+, that hydrolyzed PAF and a synthetic oxidized phospholipid. Expression of human type II PAF acetylhydrolase or S. pombe Plg7p enhanced the viability of S. cerevisiae subjected to oxidative stress. We conclude that a single-celled organism with an exceedingly spare genome still expresses an unusually discriminating phospholipase A2, and that selective hydrolysis of phospholipid oxidation products is an early, and critical, way to overcome oxidative membrane damage and oxidant-induced cell death.

Characterization of Streptococcal Platelet-Activating Factor Acetylhydrolase Variants That Are Involved in Innate Immune Evasion

“…An intracellular yeast group VII PAF-AH enhances the viability of yeast under oxidative stress (29). The spirochete Leptospira interrogans produces a PAF-AH (30).…”

The emerging roles of PAF acetylhydrolase

“…PAF has also been shown to induce apoptosis, but the mechanism underlying this function remains to be elucidated (42). S. pombe, which possesses the smallest known eukaryotic genome, still express an isoform of PAF-AH that prevents oxidant-mediated death (47). This suggests that hydrolysis of oxidized phospholipids is a primordial function of PAF-AH.…”

Oxidatively Truncated Phospholipids Are Required Agents of Tumor Necrosis Factor α (TNFα)-induced Apoptosis

“…PAF acetylhydrolases are an ancient form of protection against an oxidizing environment, with an ortholog present prior to divergence of yeast that protects these free living cells against phospholipid oxidation and oxidative death (26). Similarly, forced expression of PAFAH2 in cultured cells protects against oxidative stress (27), foam cell formation in vitro (56), neointima formation and atherosclerosis (57), and focal cerebral ischemia (58) and reduces glutamate-induced apoptosis in vitro (59).…”

“…Hydrolysis of oxidatively damaged phospholipids may be the original role of this family of phospholipases A 2 (26), and overexpression of the family member PAFAH2 in mammalian cells reduces toxicity to exogenous ROS (27).…”