ReviewDiverseubiquitinlinkagesregulateRIPkinases-mediatedinflammatoryandcelldeathsignalingAxelWitt1andDomagojVucic*,1MembersoftheRIPkinasefamilyarekeyregulatorsofinflammationandcelldeathsignalingimplicatedinmaintainingimmuneresponsesandpropertissuehomeostasis.Increasingevidencepointstopost-translationalmodificationsofRIP1,RIP2andRIP3asbeingcriticalforregulatingtheirfunction.UbiquitinationandtheE3ligases,suchasinhibitorsofapoptosis(IAP)proteinsandLUBAC,thatdirectsubstrateselectivityaswellasthedeubiquitinatingenzymes,suchasA20andOTULIN,thatreversethesemodificationsdictatetheoutcomeofRIPkinasesignaling.PerturbationofthetightlyregulatedRIP1,RIP2andRIP3ubiquitinationcanleadtosignalingdisbalanceinTNF,TLRandNOD1/2-controlledpathwaysandresultinseverehumanpathologies.Inthisreview,wefocusonthebiologicalfunctionofubiquitin-modifyingenzymesinthecontextofRIP1,RIP2andRIP3signaling.WealsodiscusstheimpactofderegulatedubiquitinnetworksinRIP1,RIP2andRIP3signalingpathwaysonhumanhealth.CellDeathandDifferentiation(2017)24,1160–1171;doi:10.1038/cdd.2017.33;publishedonline5May2017Facts�RIP1ubiquitinationisanintegralpartofTNF-mediatedassemblyoftheTNFR1-associatedsignalingcomplexandsubsequentNF-κBandMAPKactivation.�RIP1deubiquitinationimpairspro-inflammatorygeneexpressionsignalingandallowsRIP1translocationtocelldeath-promotingintracellularcomplexes.�RIP1andRIP3areubiquitinatedduringnecroptoticcelldeathsignaling.�RIP2ubiquitinationisessentialforNOD1/2-mediatedsignalingandproductionofpro-inflammatorycytokinesandchemokines.Openquestions�WhatisthefunctionalroleofRIP3ubiquitinationinTLR4signaling?�WhichE3ligase(s)mediatenecroptoticRIP1/3ubiquitination?�WhatisthephysiologicalroleofRIP1andRIP3ubiquitina-tioninnecroptosis?�WhatistheroleofRIP2E3ligasesbesideXIAPandLUBACinNOD1/2signaling?Theimmunesystemrepresentsthefirstlineofdefenseagainstinvadingpathogensordangersignalsandismediatedbypathogen-recognitionreceptors.Engagementofinflamma-torypathwaysmediatedbyToll-like(TLR),NOD-like(NLR),R...
