New Insights into the Function of IAP Proteins

Furukawa,Y.(2007).Stem Cells25,2439–2447.Li,J.,Ran,C.,Li,E.,Gordon,F.,Comstock,G., Siddiqui,H.,Cleghorn,W.,Chen,H.-Z.,Kornacker,K.,Pandit,S.K.,et al.(2008).Dev.Cell14,thisissue,62–75.Marti,A.,Wirbelauer,C.,Scheffner,M.,and Krek,W.(1999).Nat.Cell Biol.1,14–19.Vlieghe,K.,Boudolf,V.,Beemster,G.T.,Maes,S.,Magyar,Z.,Atanassova, A.,deAlmeida Engler,J.,De Groodt,R.,Inze, D.,and De Veylder,L.(2005).Curr.Biol.15,59–63.New Insights into the Function of IAP Proteins: Modulation of the MYC/MAX/MAD NetworkCasey W.Wright1and Colin S.Duckett1,2,*1Department of Pathology2Department of Internal MedicineThe University of Michigan Medical School,Ann Arbor,MI48109,USA*Correspondence:colind@DOI10.1016/j.devcel.2007.12.015A growing number of studies have revealed that the inhibitor of apoptosis(IAP)proteins play a variety of cellular roles in addition to suppression of apoptosis.A recent study in Molecular Cell demonstrates that one IAP member,c-IAP1,functions to potentiate the activity of Myc by triggering the ubiquitination and proteasomal degradation of the Myc inhibitory protein Mad1.When the inhibitor of apoptosis(iap)genes werefirst revealed in the genomes of higher eukaryotes and the term was coined,the function implied by the name frequently led to the mistaken assumption that all IAPs act to suppress apoptotic cell death. Certainly the prototype IAP,which was dis-covered in the genomes of insect viruses through an elegant screening approach designed to identify viral gene products capable of enhancing the survival of the infected cell(Crook et al.,1993),lives up to the name,but the proteins encoded by the related cellular genes actually partici-pate in a wide range of cellular activities. The recent report in Molecular Cell by Xu and coworkers(Xu et al.,2007)aptly dem-onstrates this point.Two important domains were originally identified in the baculovirus IAPs.The ba-culovirus iap repeat(BIR)is a zinc-finger-like structure,two tandem repeats of which are present in the baculovirus rgely through homology searches,the genomes of many higher eukaryotic organisms rang-ing from yeasts to human have now been shown to encode a group of proteins con-taining between one and three BIRs,and these proteins are collectively referred to as IAPs(Vaux and Silke,2005).The second domain,which is characteristically found at the extreme carboxy terminus of the pro-type baculovirus IAP,as well as of severalcellular IAPs,is the RING motif.RING-con-taining proteins have been shown to directthe ubiquitination and proteasome-medi-ated degradation of target proteins.Ini-tially,the BIRs were the focus of much in-vestigation,particularly in the mammalianX-linked IAP(XIAP)in which the BIRs andadjacent sequences have been shown todirectly bind to certain caspases,proteo-lytic enzymes which are critical executorsof the apoptotic cell death program.How-ever,a growing body of work has demon-strated the functional significance of theIAP RINGs,although the substrates of theirubiquitin ligase activities have remainedlargely elusive.In their study,Xu and colleagues(Xuet al.,2007)examine the ubiquitin ligaseproperties of c-IAP1,a broadly expressedmammalian IAP that contains three BIRsand a RING.An interesting screening ap-proach was taken to identify substratesof the E3activity of c-IAP1;specifically,testing a collection of proteins with well-established roles in tumorigenesis.Thestudy focuses on one‘‘hit’’from thisapproach:the tumor suppressor MAD1.The data support the notion that phys-iologically,MAD1levels are regulatedby polyubiquitination and proteasomaldegradation through a mechanism thatinvolves the RING-dependent ubiquitinligase activity of c-IAP1.The identification of MAD1as a targetof c-IAP1is intriguing for several reasons.A pioneering study identified c-IAP1as aputative oncoprotein that can function co-operatively with MYC in an experimentalmurine model of hepatocellular carci-noma(Zender et al.,2006).MAD1is bestknown as a repressor of MYC throughits ability to preferentially heterodimerizewith the MYC binding partner MAX(Grandori et al.,2000),and so by identify-ing MAD1as a target of c-IAP1,the studyby Xu and colleagues provides a potentialexplanation for the apparently synergistictumor-enhancing effects of combiningMYC and c-IAP1.Indeed,the study lendssupport to such a model,using transfor-mation assays in which endogenouslevels of c-IAP1,MAD1,and MYC weremodulated by overexpression and RNAinterference approaches,and the datasuggest not only that c-IAP1cooperateswith MYC in tumorigenesis,but that thiscooperativity is mediated by the antago-nism of MAD1.Importantly,the RING-me-diated ubiquitin ligase activity was shownto be required for these effects.Developmental Cell14,January2008ª2008Elsevier Inc.3Developmental Cell PreviewsAnother critically importantfinding of this study is that c-IAP1was shown to function in oncogenesis through a mecha-nism which does not appear to involve direct apoptotic inhibition or direct inter-action of the IAP with caspases.It is pos-sible that while c-IAP1might not function as a caspase inhibitor in the classical,bio-chemical sense,it might be able to target caspases for polyubiquitination,which would ultimately achieve the same effect. Additionally,recent reports have shown that c-IAP1can ubiquitinate other IAPs, and can also function as a modulator of the signaling pathways controlling the NF-k B transcription factor pathways by directing the ubiquitination of key signal-ing intermediates such as NIK(Vince et al.,2007;Varfolomeev et al.,2007), RIP(Petersen et al.,2007)and NEMO/ IKK g(Tang et al.,2003),and so collec-tively these studies underscore the biological importance of IAPs in diverse cellular processes.While these and other reports are beginning to shed light on the types of substrates that can be recognized and tar-geted by the RING-containing IAPs,we still know very little about how and whenthe ligase interacts with the substrate.The keyfinding from over a decade agothat c-IAP1is recruited to the type2tumornecrosis factor through its interaction withTRAF proteins(Rothe et al.,1995)stronglysuggests a predominantly cytosolic roleas a signal transduction intermediate,yetthe study by Xu and coworkers revealsboth a nuclear and cytosolic distributionof c-IAP1and suggests that the nuclearpool is likely responsible for the targetingof MAD1.So we have much to learn abouthow the IAPs traffic intracellularly,howthey meet their targets,and how theirubiquitin ligase activities are triggered.Nevertheless,the identification of the tar-gets of these E3ligases is an essentialfirststep in understanding the regulatory rolesof the IAPs normally,as well as in diseasestates in which the activities of these enig-matic proteins are deregulated.REFERENCESCrook,N.E.,Clem,R.J.,and Miller,L.K.(1993).J.Virol.67,2168–2174.Grandori, C.,Cowley,S.M.,James,L.P.,andEisenman,R.N.(2000).Annu.Rev.Cell Dev.Biol.16,653–699.Petersen,S.L.,Wang,L.,Yalcin-Chin,A.,Li,L.,Peyton,M.,Minna,J.,Harran,P.,and Wang,X.(2007).Cancer Cell12,445–456.Rothe,M.,Pan,M.-G.,Henzel,W.J.,Ayres,T.M.,and Goeddel,D.V.(1995).Cell83,1243–1252.Tang,E.D.,Wang,C.Y.,Xiong,Y.,and Guan,K.L.(2003).J.Biol.Chem.278,37297–37305.Varfolomeev,E.,Blankenship,J.W.,Wayson,S.M.,Fedorova,A.V.,Kayagaki,N.,Garg,P.,Zobel,K.,Dynek,J.N.,Elliott,L.O.,Wallweber,H.J.,et al.(2007).Cell131,669–681.Vaux,D.L.,and Silke,J.(2005).Nat.Rev.Mol.CellBiol.6,287–297.Vince,J.E.,Wong,W.W.,Khan,N.,Feltham,R.,Chau, D.,Ahmed, A.U.,Benetatos, C.A.,Chunduru,S.K.,Condon,S.M.,McKinlay,M.,et al.(2007).Cell131,682–693.Xu,L.,Zhu,J.,Hu,X.,Zhu,H.,Kim,H.T.,Labaer,J.,Goldberg,A.,and Yuan,J.(2007).Mol.Cell28,914–922.Zender,L.,Spector,M.S.,Xue,W.,Flemming,P.,Cordon-Cardo,C.,Silke,J.,Fan,S.T.,Luk,J.M.,Wigler,M.,Hannon,G.J.,et al.(2006).Cell125,1253–1267.Retromer Retrieves WntlessSuzanne Eaton1,*1Max Planck Institute of Molecular Cell Biology and Genetics,Pfotenhauerstrasse-108,Dresden01307,Germany*Correspondence:eaton@mpi-cbg.deDOI10.1016/j.devcel.2007.12.014Wntless is a sorting receptor required for Wnt secretion.Wntless is retrieved from endosomes to the Golgi by retromer,permitting Wntless reutilization in Wnt transport.In the absence of retromer,Wntless is degraded in lysosomes and Wnt secretion is impaired.The Wnt family of secreted signaling proteins patterns a huge variety of devel-oping tissues throughout metazoa.In this issue,and in an upcoming issue of Nature Cell Biology,work fromfive differ-ent labs addresses the mechanism by which Wntless and the retromer complex work together to promote secretion of Wnt family proteins(Belenkaya et al., 2008;Franch-Marro et al.,2008;Pan et al.,2008;Port et al.,2008;Yang et al., 2008).The conserved requirement for the mul-tiple pass transmembrane protein Wntlessin Wnt secretion wasfirst reported in2006by multiple groups working with Drosoph-ila melanogaster,Caenorhabditis elegans,and human tissue culture cells(reviewedin Hausmann et al.,2007).Wntless hasbeen variously called Evenness Interrup-ted(Evi)and Sprinter in Drosophila andMOM-3/MIG-14in C.elegans;here,I willrefer to it as Wntless for the sake of clarity.In Wntless mutants,Wnts accumulateinside the cells that make them and bothsurface delivery and secretion are im-paired.Wnt secretion appears to be theonly nonredundant function for Wntless;Drosophila wntless mutants,which donot secrete normal levels of the DrosophilaWnt Wingless(Wg),can be rescued to via-bility by wntless expression in Wingless-producing cells.Retromer wasfirst identified in yeastas being important for efficient traffickingof lysosomal hydrolases to the vacuole.4Developmental Cell14,January2008ª2008Elsevier Inc.Developmental Cell Previews。