A Novel Mechanism Study Of Celastrol The Ligand Of Nur77

Celatrol,artemisinin,triptolide,capsaicin and curcumin are considered as the promise of turning traditional medicines into modern drugs by Cell paper in 2007.Celastrol has attracted increasing interest recently and reported for its potent anti-inflammatory activities in many inflammatory diseases,including obesity.However,the specific target and the mechanism by which celastrol exert its beneficial effects remain largely unknown,which become a huge challenge for modern drug development.It is urgent for scientists to search specific target and molecular mechanism of celastrol,which is the major significance of this phD thesis.Mitochondria play an integral role in cell death,autophagy,immunity and inflammation.Mitophagy,a selective form of autophagy to remove dysfuctional damaged mitochondria from inflammation,represents an important mechanism to maintain a successful inflammatory response,and thus to reverse pathological status in chronic inflammatory diseases by yet pooly understood mechanisms.The orphan nuclear receptor Nur77(also called TR3 and NGFIB),as an early response gene,plays an integral role in plethora of cellular processes including survival,apoptosis,inflammation and autophagy in response to diverse stimuli such as mitogens,cytokine,stress,and metabolic and apoptotic disease.Our group has reported firstly that Nur77 could translocate to mitochondria to modulate its activities in response to apoptotic stimuli in the journal of Scinece(2000),Cell(2004)and Cancer Cell(2008).Therefore,Nur77 may be one promising target to regulate inflammtion and mitophagy.Here,we report that celastrol,a potent anti-inflammatory pentacyclic triterpene isolated from Tripterygium Wilfordi(thunder god vine)plant,binds Nur77 to inhibit inflammation and induce autophagy in a Nur77-dependent manner.Celastrol promotes Nur77 translocation from the nucleus to mitochondria where it interacts with tumor necrosis factor receptor-associated factor 2(TRAF2),a scaffold protein and E3 ubiquitin ligase important for inflammatory signaling.The interaction is mediated by an LxxLL motif in TRAF2 and results in not only inhibition of TRAF2 ubiquitination but also Lys63-linked Nur77 ubiquitination.Under inflammatory conditions,ubiquitinated Nur77 resides at mitochondria,rendering them sensitive to autophagy,an event involved interaction of Nur77 with the ubquitin-associated(UBA)domain of p62/SQSTM1.The specific interaction of modified Nur77 with p62 and LC3 ensures selective elimination of damaged mitochondria.This project has been finished and published in the journal of Molecular Cell.Together,our results identify celastrol as a new Nur77 modulator with promising therapeutic potential,which induce Nur77 interaction with TRAF2 to alleviate inflammation by promoting mitochondrial ubiquitination and autophagy.This thesis reveals the specific target and the mechanism by which celastrol exert its beneficial effects,which can be recognized as the milestone of turning traditional medicines into modern drugs.This study provide theoretical basis for develpment of celastrol as a powerful and widely used drug to treat many inflammatory diseases including obesity.