Exploiting and Subverting Tor Signaling in the Pathogenesis of Fungi, Parasites, and Viruses 英文参考文献.docVIP

Pearls ExploitingandSubvertingTorSignalinginthe PathogenesisofFungi,Parasites,andViruses CeceliaA.Shertz,MariaE.Cardenas* DepartmentofMolecularGeneticsandMicrobiology,DukeUniversityMedicalCenter,Durham,NorthCarolina,UnitedStatesofAmerica TorSignalingSensesNutrientsandGrowth FactorstoGovernPathwaysInvolvedinthe PathogenesisofFungi,Parasites,andViruses whichisaregulatorofmorphogeneticprocessessuchastheyeastto hyphaltransitionandbiofilmformation[9,10].Althoughatpresent itisunclear howMds3acts,ithas beensuggestedthatMds3isa negativeregulatorofTor1[11].TreatmentwiththeTorinhibitor rapamycin inhibits hyphal growth on solid media and causes extensive cellular aggregation and flocculation. These results are consistentwiththemodelthatTor1positivelycontrolsfilamentation andnegativelyregulatescellularadhesion(Figure1A)[7]. Ineukaryotesfromyeasttohumans,theTorsignalingcascade respondstonutrientsandgrowthfactorstoorchestratecellgrowth and proliferation. The central elements of this signaling cascade are the Tor protein kinases, which are the targets of the potent anti-proliferative and immunosuppressive natural product rapa- mycin[1].Most organisms,includingmammals,express asingle Tor kinase; however, the yeasts Saccharomyces cerevisiae and SchizosaccharomycespombecontaintwoTorhomologs[2],andthree andfour(twoclassicalTorkinasesandtwoTor-likekinases)have beenidentifiedintheprotozoansLeishmaniamajorandTrypanosoma brucei, respectively [3,4]. The Tor kinases interact with other RapamycinPotentlyInhibitsTrypanosome ProliferationbyBlockingTORC2Assembly T. brucei is a protozoan parasite responsible for causing ,500,000 annual infections in Africa that result in sleeping sickness, with devastating socioeconomic effects. T. brucei has a complexlifecyclethatdevelopsintwodifferenthosts(thetsetsefly andvertebrates)andseveralnicheswithinthesehosts.Nutritional stress encountered in the insect triggers the development of the non-infectiousprocyclictrypomastigoteintotheinfectivemetacy