Editorial Overview: Molecular immunology: Targeting the immune system
Marcus Groettrup and Huib Ovaa
It is only four decades agothat immunologists werenicknamed by their colleagues from biochemistry ‘immunosophists’ because they loved to discusstheorieshowtheimmunesystemmayworkatthechalkboard.This passion wasprobablynourishedbythelackof mechanisticandmolecular insightsintoexcitingphenomenaof theimmunesystem.Importantques- tionswere:howareantigensrecognized,howisthehugediversityofantigen receptors generated,how isautoimmunityavoided,howdoimmunecells knowwheretogo,andwhydowegetimmunetoapathogen?Immunology wasstudiedbyasmallcommunityinanivorytowerwithlittleinterestfrom chemistsorpharmaceuticalindustry.Thishasdramaticallychangedinthe meantime.Theexponentiallygrowingbodyofknowledgeaboutmolecular mechanismsinimmunologyhasrevealedveryattractivetargetsforpharma- cological modulation and has long caught the interest of pharmaceutical companies.Today’stherapeuticsuccessofsmallmoleculesandbiologicals, especiallymonoclonal antibodies, in cancertherapy or thesuppression of autoimmunity,allergyandtransplantrejectionisimpressive.Nevertheless, there isampleroomfor improvementconsideringthatancientdrugswith lots of adverse side effects like corticosteroids are still prescribed most frequently.
TheGuestEditorsofthisfirstsectionon‘MolecularImmunology’inCurrent Opinion inChemical Biology feelthat thisis aperfectoccasion toinitiate a separatesectionwherechemicalbiologymeetsimmunology.Unfortunately, thewealth of concepts,abbreviations andcellsurface‘CD’receptormol- ecules pose achallenge to authors who wantto explain to achemist the immunologicalcontextofwhyanemergingtargetissoattractive andthis in a review of only 2000 words. We think that the authors of this first MolecularImmunologysectionhavedoneasplendidjobonthis.Thetopics whichhavebeencoveredarecertainlyonlyaselectionofthemanytargetsto choose frombutatleastitisastart.
AllroadsleadtoRome,sowecannotmissoutonRomeinthissection.What is Rome? The obvious guess is the Nuclear Factor ‘kappa-light-chain- enhancer’ of activated B cells (NF-kB). There is no signal transducer and transcriptionfactorontowhichso manydifferentsurfacereceptorsof immunecellsculminate.NF-kBiscrucialfortheinitiationbutalsoforthe limitationof apro-inflammatoryimmuneresponse. Pathogensensing toll- likereceptors(TLRs),cytokinereceptors,antigenreceptorsandmanymore triggeruponligandstimulationthemigrationofthetwosubunitsofNF-kB, p50 and p65, from the cytoplasm to the nucleus to activate genes. It is beyond thescopeofaconcisereviewto coverNF-kBactivationbyallof these receptors. This is why Wertz reviews the regulation of NF-kB Marcus Groettrup
DivisionofImmunology,Departmentof Biology,UniversityofKonstanz,
Universita¨tsstrasse10,D-78457Konstanz, Germany
e-mail:Marcus.Groettrup@uni-konstanz.de
MarcusGroettrupisaprofessorfor ImmunologyattheUniversityofKonstanz.
Hisinterestisfocussedonantigen processingbytheproteasome.Hehas discoveredthepre-Tcellreceptorand recentlyfoundanewfunctionofthe immunoproteasomeinthepathogenesisof autoimmunediseases.Moreover,his laboratoryisworkingonthefunctionofthe ubiquitin-likemodifierFAT10intargeting antigenstothe26Sproteasomeandin antigenpresentation.
Huib Ovaa
DivisionofCellBiology,TheNetherlands CancerInstitute,Plesmanlaan121,1066CX Amsterdam,TheNetherlands
e-mail:H.Ovaa@nki.nl
HuibOvaaisgroupleaderattheNetherlands CancerInstitute(NKI)inAmsterdamand professorofchemicalbiologyofpost- translationalmodificationsatLeiden University,theNetherlands.Hisinterestgoes todrugdiscoveryandtoubiquitinsignaling, ubiquitin-mediatedproteolysisandantigen presentation.Hislabhasdeveloped technologiesforthetotalchemicalsynthesis ofubiquitinchainsandubiquitylated substratesandawiderangeofactivity-based probes.
Konstanzer Online-Publikations-System (KOPS) URL: http://nbn-resolving.de/urn:nbn:de:bsz:352-0-275635 Erschienen in: Current Opinion in Chemical Biology ; 23 (2014). - S. V-VII
https://dx.doi.org/10.1016/j.cbpa.2014.10.012
activationbyoneof thesereceptors,thetumornecrosis factorreceptor-1(TNFR1).Attheendofthecascadean inhibitorproteinof NF-kB(IkB),which keepsthep50/
p65heterodimerinthecytoplasm,isfirstphosphorylated andthenpolyubiquitylatedinordertobesentfordegra- dation to the 26S proteasome. To achieve this goal a complex interplay of phosphorylations/dephosphoryla- tionsandubiquitylations/deubiquitylationsoccurswhich decidesontheextentofNF-kBactivation.Linearhead- to-taillinkedubiquitinchainsandubiquitinchainslinked viaK63ofubiquitinserveasassemblyscaffoldstobring togethertherightkinasesandsubstrates.I.Wertzintro- ducestheinvolved deubiquitylasesas naturalinhibitors ofNF-kBandcoversthebiologicalsandsmallmolecules which have been designed mostly to inhibit TNFR1 mediated activation of NF-kB. On the way not from TNFR1butfromtheantigenreceptorsofBandTcells to NF-kB is where the paracaspase MALT1 plays an importantrole.Hailfinger etal. reviewthecentral func- tion of MALT1 in NF-kB activation but also in the development of some B cell lymphomas and the mucosa-associatedlymphoidtissue (MALT)lymphoma, afterwhichthisproteasewasnamed.Itisdescribedhow MALT1isactivatedphysiologically interestinglyalso byubiquitylation butalsopathologicallybymutations inlymphomas.Assaysformonitoringtheproteaseactivity of MALT1 are introduced in this review as well as recentlydevelopedsmallmoleculeinhibitorsofMALT1 activity.
Deubiquitylatingenzymes(DUBs)likeA20,CYLDand OTULIN are pivotal for the regulation of NF-kB sig- naling, but these are only three out of approximately 80 DUBs in the human genome. The Ovaa laboratory focussesonthesynthesisofactive-sitedirectedprobesfor DUBswhichcanbeusedtolabelandisolatethemfrom cellsandtissues.TogeneratetheseprobestheC-termi- nusofubiquitinoraubiquitin-likemodifierisequipped withachemicalwarheadlikevinylmethylester,alkylbro- mide,ormorerecentlypropargylwhichbindtoactivesite cysteineresidueswhichmostDUBsbearintheircatalytic center. These activity-based probes can be generated fromrecombinantubiqutin-inteinfusionproteinsorthey canbederivedviacompletechemicalsynthesis.Intheir review, Ekkebus et al. also review how ubiquitin chain specific probes can be generated by native chemical ligation. Ubiquitin chains canbe linked via any of the seven lysines of ubiquitin and DUBs can discriminate betweenthembasedonwhichlysineisusedforisopep- tidebondformation.Thisimplicatesthatlinkagespecific DUBscanbespecificallylabeledandidentifiedwiththe helpofubiquitinchain specificprobes.
Adenosineis oneof thecellularkey building blocks.It actsinitselfasasignalingmolecule,itisaconstituentof RNA, and as a phosphotriester (ATP) it provides the energythatdrivesmanycellularprocesses.Itcanalsobe
foundaspartof post-translationalproteinmodifications.
ProteinscanbemodifiedthroughADPribosylationand AMPylation. The study of these modifications needs a goodsetofchemicaltools.WestcottandHangprovidean overviewofthereagentsdescribedintheliteraturethat help to study these modifications and they discuss the typeofreagentsthatremaintobedeveloped.Indoingso theauthorsfocustheirreviewontheimportanceofADP- ribosylation and AMPylation in infection at the host pathogeninterface.
The proteasome is an abundant proteolytic cellular machine,which is responsible for theturn-over of ubi- quitylatedproteins.Theproteasomecontainssixcatalytic sites(3differentactivesitesubunitsinduplo)andvarious proteasomespeciesexistsuchastheimmunoproteasome that contain differentactive site subunits. The protea- someisalso abona fidedrugtarget: thebroadspectrum proteasomeinhibitorsbortezomibandcarfilzomibarefor example used in the treatment of multiple myeloma.
Despitethissuccessmuchistobelearnedfrominhibition ofdistinctcatalyticsites.KisselevandGroettrupreview thecurrent state-of-the-artin the design of subunit se- lectiveinhibitorsandexplainwhatmedicalneedsmaybe metwiththeseinhibitorssuchas thetreatmentof auto- immune diseases with selective immunoproteasome inhibitors.
Proteasesaspotentialdrugtargetsarealsoinvolvedinthe processingofproteinantigenstopeptidicTcellepitopes presented onmajor histocompatibility complex (MHC) class I and class II molecules for the stimulation of cytotoxic T lymphocytes (CTL) and T helper cells (Th),respectively.Theirinhibitionmayallowthemodu- lation of T cell responses. Antigen processing for the MHC class I pathway is initiated by the proteasome followed by processing of the released polypeptides mostly byaminopeptidases in thecytoplasm and endo- plasmicreticulum(ER)totrimthemforaperfectfitinto thepeptidebindinggrooveofclassImolecules.Stratikos reviewsinhisarticlethispathwayandhow aminopepti- dases canbe inhibited with afocus on theER amino- peptidases (ERAP)1 and 2. Knock out mice lacking ERAP1 have shown that its activity markedly affects the peptide repertoire presented on class I molecules.
InhisreviewE.Stratikosexplainshowphosphinicpseu- dopeptide transition analogs can be used to inhibit ERAPs and to enhance CTLresponses to cancer cells.
Another challenging taskisto achieve immunomodula- tionthroughthe selectiveinhibition of over adozen of differentcathepsins.Cathepsinsarecentrallyinvolvedin antigenprocessingintheendolysosomeforpresentation ofpeptidesonMHCclassIImolecules.VanKasterenand Overkleeft outline in their review how the different cathepsins operate during processing of theMHC class II invariant chain which accompanies MHC class II molecules ontheir wayfrom the ER to the endosome.
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Theinvariantchainblocksthepeptidebindinggrooveof classIImoleculesandneedstobedegradedinastepwise fashiontoallowpeptideantigenstobindtoclassII.The delicatebalancebetweenpeptideepitopeproductionand destruction in the class II loading compartment is explainedandhowinhibitorsofthedifferentcathepsins can contribute to the preservation of antigen and enhancement of antigen presentation. That cathepsin inhibition can also affect the functional maturation of endosomal toll like receptors through cathepsin K mediatedlimitedproteolysisisconsideredas well.
Although peptideantigen presentationby MHCclass I and class II complexes has been studied for many decades, the presentation of lipid antigens has been studied to a lesser extent. A review has been contrib- utedtothisissuebyLayreetal. wherethepresentation of non-peptide antigens to T-cellsis discussed in great detail. CD1 and MR1 proteins can present lipids and other non-peptidic small molecules to lipid- and small molecule reactiveT-cells. Thedevelopment ofspecific CD1andMR1tetramershasnowalsoenabledthestudy of this subset of T-cells opening a new field where many discoveries are expected to be made in thenear future.
Areviewwithaclearfocusoncancerimmunotherapyis contributedtothisissuebyBoymanandcolleagues.They outlinehowinterleukin(IL)-2hasbeenusedinthepastto treatthe‘immunogenic’cancersmelanomaandrenalcell carcinoma. The side effects of systemic IL-2 adminis- tration, however, limit the therapeutic success. The attempts to avoid this dilemma include the use of mutatedIL-2molecules,theIL-2muteinsorsuperkines, theuseofIL-2fusionproteins,aswellastheuseofIL-2 antibodycomplexes.Thesereagents bindselectivelyto
thethreechainsoftheIL-2receptorwhichdifferentially affectsimmunosuppressiveregulatoryTcellsandeffec- tor T cells. T cells reactive against cancer tissues can thereforebeactivatedandexpanded.Rosaliaetal.explain and summarize in helpful tables which IL-2and IL-15 variantsbindwhichIL-2Rchainsandhowfartheirpre- clinical andclinicalevaluationhasproceeded todate.
Sundbergetal.discussnovelopportunitiesforthetreat- ment of immune disorders through small-molecule mediated control of cytokine function. Although protein-based drugs have been proven effective in the manipulation ofcytokine functionand thetreatmentof autoimmuneand autoinflammatorydiseases, suchdrugs cannoteasilymodulateintracellulartargets.Theauthors specificallydiscusstheimportanceofthedevelopmentof smallmoleculemodulatorsofcytokinefunctionandthey provideanexcellentoverviewofcurrentsmallmolecules that doso together with theirtargets. The authors also discuss emerging targets and how innovations in small molecule science such as DNA-encoded synthesis will help to lift traditionaldrug discoveryapproachesto the nextlevel.
AttheendofthisEditorialOverview,theGuestEditors of thisfirstsectionon‘Molecular Immunology’,Marcus Groettrup and HuibOvaa, would like to thank allcon- tributorsfortheirexcellentreviewsandsmoothcoopera- tion.Impressiveprogresshasbeenmadeinrecentyearsin theareasreviewedinthisissue.Weareawarethattheten reviewsincludedinthissectionbyfardonotcoverallthe importantareasof‘MolecularImmunology’whereinter- esting new concepts, drug targets,and therapeutic ave- nuesemerge.Thisnourishesourhopethatthisissuewill bethefirstofalongandprosperousseriesofissuesonthis excitingtopic.
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