Ubiquitin C-terminal hydrolase 37 regulates Wnt/β-catenin pathway duing Xenopus gastrulation

Abstract

TheTcf/LeffamilyoftranscriptionfactorsmediatestheWnt/β-cateninpathwaythatisinvolvedinawiderangeofbiologicalprocesses,includingvertebrateembryogenesisanddiversepathogenesis.Post-translationalmodifications,includingphosphorylation,sumoylationandacetylation,areknowntobeimportantfortheregulationofTcf/Lefproteins.However,theimportanceofubiquitinationandubiquitin-mediatedregulatorymechanismsforTcf/Lefactivityarestillunclear.Here,wenewlyshowthatubiquitinC-terminalhydrolase37(Uch37),adeubiquitinase,interactswithTcf7(formerlynamedTcf1)toactivateWntsignalling.BiochemicalanalysesdemonstratedthatdeubiquitinatingactivityofUch37isnotinvolvedinTcf7proteinstabilitybutisrequiredfortheassociationofTcf7totargetgenepromoterinbothXenopusembryoandhumanlivercancercells.InvivoanalysesfurtherrevealedthatUch37functionsasapositiveregulatoroftheWnt/β-cateninpathwaydownstreamofβ-cateninstabilizationthatisrequiredfortheexpressionofventrolateralmesodermgenesduringXenopusgastrulation.OurstudyprovidesanewmechanismforchromatinoccupancyofTcf7anduncoversthephysiologicalsignificanceofUch37duringearlyvertebratedevelopmentbyregulatingtheWnt/β-cateninpathway.