Ablation of Arginylation in the Mouse N-End Rule Pathway Loss of Fat, Higher Metabolic Rate, Damaged Spermatogenesis, and Neurological Perturbations 英文参考文献.docVIP

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Ablation of Arginylation in the Mouse N-End Rule Pathway Loss of Fat, Higher Metabolic Rate, Damaged Spermatogenesis, and Neurological Perturbations 英文参考文献.doc

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Ablation of Arginylation in the Mouse N-End Rule Pathway Loss of Fat, Higher Metabolic Rate, Damaged Spermatogenesis, and Neurological Perturbations 英文参考文献

AblationofArginylationintheMouseN-EndRule Pathway:LossofFat,HigherMetabolicRate,Damaged Spermatogenesis,andNeurologicalPerturbations ChristopherS.Brower,AlexanderVarshavsky* DivisionofBiology,CaliforniaInstituteofTechnology,Pasadena,California,UnitedStatesofAmerica Abstract IntheN-endrulepathwayofproteindegradation,thedestabilizingactivityofN-terminalAsp,Gluor(oxidized)Cysresidues requires their conjugation to Arg, which is recognized directly by pathway’s ubiquitin ligases. N-terminal arginylation is mediatedbytheAte1arginyltransferase,whosephysiologicalsubstratesincludetheRgs4,Rgs5andRgs16regulatorsofG proteins. Here, weemployedtheCre-lox techniquetouncover new physiologicalfunctions of N-terminalarginylation in adultmice.WeshowthatpostnataldeletionofmouseAte1(itsunconditionaldeletionisembryoniclethal)causesarapid decrease of body weight and results in early death of ,15% of Ate1-deficient mice. Despite being hyperphagic, the survivingAte1-deficientmicecontainlittlevisceralfat.Theyalsoexhibitanincreasedmetabolicrate,ectopicinductionof theUcp1uncouplingproteininwhitefat,andareresistanttodiet-inducedobesity.Inaddition,Ate1-deficientmicehave enlarged brains, anenhanced startle response, arestrikingly hyperkinetic, and areprone toseizures andkyphosis. Ate1- deficient males are also infertile, owing to defects in Ate12/2 spermatocytes. The remarkably broad range of specific biological processes that are shown here to be perturbed by the loss of N-terminal arginylation will make possible the dissectionofregulatorycircuitsthatinvolveAte1andeitheritsknownsubstrates,suchasRgs4,Rgs5andRgs16,orthose currentlyunknown. Citation: Brower CS, Varshavsky A (2009) Ablation of Arginylation in the Mouse N-End Rule Pathway: Loss of Fat, Higher Metabolic Rate, Damaged Spermatogenesis,andNeurologicalPerturbations.PLoSONE4(11):e7757.doi:10.1371/journal.pone.0007757 Editor:ImmoA.Hansen,NewMexicoStateUniversity,UnitedStatesofAmerica ReceivedSeptember1,2009;AcceptedOctober13,2009;Publish