《The E3 Ubiquitin Ligase gp78 Protects against ER Stress in Zebrafish Liver.》.pdf

z．Cheneta1．／JournalofGeneticsandGenomics41368 ofgp78expression in zebrafishembryosdoesnotresultin contribute to hepatic steatosismay depend on the cellular morphologicalphenotypesundernormalphysiologic condi— eventthatelicitsUPR．Interestingly，overexpressionofBiP-an tions．Thisisincontrasttoapreviousreportthatknockoutof inhibitorofUPR，hasbeenshowntoprotectagainstinsulin HMG—CoAreductasedegradationprotein。l(Hrd1．alsonamed and ER stress．induced hepatic steatosis fWerstuck et a1．． asSYVN1，thehumanorthologofHrd1)，agp78homologE3 2001)．Importantly，overexpressionofBiPinmicealsoin— ubiquitinligase．inmiceresultsinembryoniclethalitydueto hibitsthe activation ofSREBP．1c fRon and Walter．2007； severeanemia(Yagishitaeta1．，2005)．whichisprobablycaused Kammoun etal一2009)．Itisalsopossiblethatgp78may byenhancedapoptosisofembryonicerythrocytesintheliver directly regulate Srebp expression through modifying un— (Amanoeta1．，2003；Yagishitaeta1．，2005)．Importantly，our knownsubstrateproteins．Thispossibilityissupportedbythe study inzebrafish isinagreementwiththereport inCaeno— factthatOverexDressiOnofthewild—typegp78in1iverreduced rhabditiselegansthatdeletionofgp78ortholog． ，Z一1．hasno hteexpressionofSrebptargetgenestothelevelsbelow hte phenotype(Sasagawaeta1．，2007)．Thedifferentphenotypes basallevelofexpression．However,arecentstudyshowedthat rfom lossofgp78orHrd1functionmayreflecttheirdifferences inhibitionofgp78functionin1iverbyliver．specificdeletionof insubstratespectrums．Comparedwithgp78，Hrdlmaycovera gp78genedecreasedSrebptargetgeneexpressionandreduced widerspectrum ofsubstrates．Lossofgp78functionmaybe lipidlevels(Liueta1．，2012)．Themechanismunderlyingthis compensatedbythepresenceofHrd1．Howeve~gp78cannot discrepancyremainstobedetermined． replaceHrdlbecauseknockoutofHrd1aloneresultsinearly embryoniclethality(Yagishitaeta