1、Leading EdgePreviewsTransforming Lipoxygenases:PE-Specific Enzymes in DisguiseLing F.Ye1and Brent R.Stockwell1,2,*1Department of Biological Sciences2Department of ChemistryColumbia University,550 West 120thStreet,MC4846,New York,NY 10027,USA*Correspondence:bstockwellcolumbia.eduhttps:/doi.org/10.101
2、6/j.cell.2017.10.006InthisissueofCell,Wenzeletal.solvealong-standingmysteryregardinghowdamagetocellmem-branes occurs during ferroptosis,an iron-dependent form of regulated cell death.They found thatlipoxygenases are like Transformer toys,being converted from one enzyme type to another in thepresence
3、 of the protein PEBP1.Cells are bounded by greasy lipid mole-cules that act as a barrier to water,sepa-rating different compartments of the cell,as well as separating the outside worldfrom the inside of the cell(Agmon andStockwell,2017).The most commonclass of membrane lipids is built from acombinat
4、ion of two kinds of molecules:apolarheadgroupthatcontainstheelement phosphorus and one or morefatty acid tails that contain a long stringofcarbonatoms.Onceconstructed,these lipids are referred to as phospho-lipids.The fatty acid part of the phospho-lipid can be saturated(meaning that thereare no car
5、bon-carbon double bonds),monounsaturated(meaning that there isonecarbon-carbondoublebond),orpoly-unsaturated(meaning that there is morethan one carbon-carbon double bond);only the latter species is sensitive to re-acting with oxygen in a chemical reactionreferred to as peroxidation(Gaschler andStock
6、well,2017).It has been previously established thatcell death by ferroptosis is a result ofsuchlipidperoxidation(Yangetal.,2016;Yang and Stockwell,2016).In thischemical reaction,oxygen is added topolyunsaturated tails of phospholipids incell membranes,creating new types ofmolecules known as lipid hyd
7、roperox-ides,as well as other derivative speciesthat may interfere with the assembly andstructure of cellular lipid membranes.Insome cases,this process can be cata-lyzed by a class of enzymes known aslipoxygenases.While the physiologicalfunctions of lipoxygenases are numerous,they are perhaps best k
8、nown for their rolein generating leukotrienes,which are car-bon-rich lipid signaling molecules thatplayimportantrolesininflammatorysignaling,such as regulating the releaseofhistamineandactivatingotherimmuneresponses(HaeggstromandFunk,2011).Recently,several researchgroups discovered a central role fo
9、r theseenzymes in promoting ferroptosis;forexample,cells became resistant to thisform of cell death as a result of lipoxyge-nase gene knockdown(Friedmann Angeliet al.,2014;Kagan et al.,2017;Yanget al.,2016).However,animportantquestionregarding lipoxygenases functioning inferroptosis remained unanswe
10、red untilnow.Lipoxygenases are known to act onfree polyunsaturated fatty acids,not onpolyunsaturated fatty acids that havebeen incorporated into more complexmembrane phospholipids.Nonetheless,it has been found that the peroxidation inferroptosis occurs directly on membranephospholipids.How lipid per
11、oxidation oc-curs on phospholipids through the actionof lipoxygenases during ferroptosis hasremained a mystery.Moreover,outofmanydifferenttypes of membrane phospholipids,onein particularphosphatidylethanolamine(PE)is predominantly peroxidized dur-ing ferroptosis(Kagan et al.,2017).Howthisspecificpho
12、spholipidspeciesisselected for peroxidation by lipoxyge-nases has been another key question.OnceperoxidizedPEmoleculesareformed,they act as death signals thatnavigatecellstowardferroptosisandsub-sequent cell death.Therefore,unravelingthe puzzle of how they are generated iscrucial in understanding on
13、e of the pivotalmechanisms of this form of cell deathand the strategies for controlling it.Thisis particularly important because ferrop-totic cell death has been implicated inseveral human diseases,such as acutekidney injury(Linkermann et al.,2014),other degenerative disorders(Li et al.,2017),and se
14、veral forms of cancer(Yangand Stockwell,2016).Therefore,betterinsightintothemechanismsdrivingthis form of cell death may provide thekey to the development of a new class oftherapeutics.Usinganinterdisciplinaryapproachcombiningbiochemical methods,compu-tational modeling,and fluorescence mi-croscopy,W
15、enzel et al.(2017,this issueof Cell)found that a protein previouslystudied only in the context of protein ki-nase cascades,PEBP1,can unexpect-edly associate with lipoxygenases suchas 15LO1 and 15LO2 to change their sub-stratespecificity,allowingthemtodirectlyreact with the polyunsaturated tails ofph
16、ospholipids already incorporated intocell membranes.Like the Transformertoys that are robots in disguise,these lip-oxygenasesarePE-phospholipid-spe-cific enzymes in disguise.The binding ofPEBP1 allows these lipoxygenases to ac-quire specificity for the PE phospholipidsthat are key to ferroptosis(Fig
17、ure 1).This discovery was facilitated usingglobalredoxphospholipidomics,withwhich the authors evaluated the phos-pholipid composition of cells by com-paring the overall abundance of oxidizedPE relative to other oxidized phospholipidCell 171,October 19,2017 2017 Elsevier Inc.501species in cells eithe
18、r with or withoutPEBP1-15LO complexes.These findingssolved two mysteries in one fell swoopand illuminated a new key regulator of fer-roptosis in a major advance for thisnascent field.Wenzel et al.(2017)further highlightedtherelevanceofthisworktohumanhealthand disease by identifying evidence ofPEBP1-
19、15LO-complex-driven lipid per-oxidation in the context of asthma,acutekidney injury,and traumatic brain injury,demonstrating that these disease statesare at least partially caused by PEBP1-15LO activity and resulting ferroptoticcell death.This discovery opens the door forfurther efforts to examine t
20、he suitabilityof the PEBP1-15LO complex as a drugtarget.For example,small molecules dis-rupting either 15-lipoxygenases,PEBP1,or the interaction between the two pro-teins could act as inhibitors of PE peroxi-dation and ferroptotic cell death,which inturn can potentially be used clinically totreat pa
21、tients with numerous degenera-tive diseases.REFERENCESAgmon,E.,and Stockwell,B.R.(2017).Curr.Opin.Chem.Biol.39,8389.Friedmann Angeli,J.P.,Schneider,M.,Proneth,B.,Tyurina,Y.Y.,Tyurin,V.A.,Hammond,V.J.,Her-bach,N.,Aichler,M.,Walch,A.,Eggenhofer,E.,et al.(2014).Nat.Cell Biol.16,11801191.Gaschler,M.M.,a
22、nd Stockwell,B.R.(2017).Bio-chem.Biophys.Res.Commun.482,419425.Haeggstrom,J.Z.,and Funk,C.D.(2011).Chem.Rev.111,58665898.Kagan,V.E.,Mao,G.,Qu,F.,Angeli,J.P.,Doll,S.,Croix,C.S.,Dar,H.H.,Liu,B.,Tyurin,V.A.,Ritov,V.B.,et al.(2017).Nat.Chem.Biol.13,8190.Li,Q.,Han,X.,Lan,X.,Gao,Y.,Wan,J.,Durham,F.,Cheng,
23、T.,Yang,J.,Wang,Z.,Jiang,C.,et al.(2017).JCI Insight 2,e90777.Linkermann,A.,Skouta,R.,Himmerkus,N.,Mulay,S.R.,Dewitz,C.,DeZen,F.,Prokai,A.,Zuchtriegel,G.,Krombach,F.,Welz,P.S.,et al.(2014).Proc.Natl.Acad.Sci.USA 111,1683616841.Wenzel,S.E.,Tyurina,Y.Y.,Zhao,J.,St.Croix,C.M.,Dar,H.H.,Mao,G.,Tyurin,V.A
24、.,Anthonymu-thu,T.S.,Kapralov,A.A.,Amoscato,A.A.,et al.(2017).Cell 171,this issue,628641.Yang,W.S.,and Stockwell,B.R.(2016).TrendsCell Biol.26,165176.Yang,W.S.,Kim,K.J.,Gaschler,M.M.,Patel,M.,Shchepinov,M.S.,and Stockwell,B.R.(2016).Proc.Natl.Acad.Sci.USA 113,E4966E4975.Figure 1.PEBP1 Associates wit
25、h Lipoxygenases and Allows Them to Generate a SpecificLipid Peroxide that Promotes Ferroptosis(A)The unbound enzyme acts on free fatty acids.(B)Bound to PEBP1,lipoxygenases acquire the ability to convert membrane phosphatidylethanolamine(PE)to its oxidized form,leading to ferroptotic cell death.502Cell 171,October 19,2017