HILI Inhibits TGF-β Signaling by Interacting with Hsp90 and Promoting TβR Degradation 英文参考文献.docVIP

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HILI Inhibits TGF-β Signaling by Interacting with Hsp90 and Promoting TβR Degradation 英文参考文献.doc

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HILI Inhibits TGF-β Signaling by Interacting with Hsp90 and Promoting TβR Degradation 英文参考文献

HILIInhibitsTGF-bSignalingbyInteractingwithHsp90 andPromotingTb RDegradation KunZhang1.,YiluLu1.,PingYang1.,ChaoLi1,HuaqinSun2,DachangTao1,YunqiangLiu1, SizhongZhang1,YongxinMa1* 1Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China, 2Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Institute of Women and Children’s Health, West China Second University Hospital, SichuanUniversityChengdu,China Abstract PIWIL2,calledHILIinhumans,isamemberofthePIWIsubfamily.ThissubfamilyhashighlyconservedPAZandPiwidomains andisimplicatedinseveralcriticalfunctions,includingembryonicdevelopment,stem-cellself-renewal,RNAsilencing,and translationalcontrol.However,theunderlyingmolecularmechanismremainslargelyunknown.Transforminggrowthfactor- b(TGF-b)isasecretedmultifunctionalproteinthatcontrolsseveraldevelopmentalprocessesandthepathogenesisofmany diseases.TGF-bsignalingisactivatedbyphosphorylationoftransmembraneserine/threoninekinasereceptors,TGF-btypeII (TbRII),andtypeI(TbRI),whicharestabilizedbyHsp90viaspecificinteractionswiththismolecularchaperone.Here,we presentevidence thatHILI suppresses TGF-bsignaling byphysically associatingwithHsp90 inhuman embryonickidney cells (HEK-293). Our research shows that HILI mediates the loss of TGF-b-induced Smad2/3 phosphorylation. We also demonstrate that HILI interacts with Hsp90 to prevent formation of Hsp90-TbR heteromeric complexes, and improves ubiquitinationanddegradationofTbRsdependentontheubiquitinE3ligaseSmurf2.Thisworkrevealsacriticalnegative regulationlevelofTGF-bsignalingmediatedbyHILI(humanPIWIL2)byitsabilitytointeractwithHsp90andpromoteTbR degradation. Citation:ZhangK,LuY,YangP,LiC,SunH,etal.(2012)HILIInhibitsTGF-bSignalingbyInteractingwithHsp90andPromotingTbRDegradation.PLoSONE7(7): e41973.doi:10.1371/journal.pone.0041973 Editor:Dong-YanJin,UniversityofHongKong,HongKong ReceivedMarch2,2012;AcceptedJune26,