title: Grail controls Th2 cell development by targeting STAT6 for degradation.
abstract: T helper (Th)-2 cells are the major players in allergic asthma; however, the mechanisms that control Th2-mediated inflammation are poorly understood. Here we find that enhanced expression of Grail, an E3 ubiquitin ligase, in Th2 cells depends on interleukin (IL)-4-signalling components, signal transducer and activator of transcription 6 (Stat6) and Gata3, that bind to and transactivate the Grail promoter. Grail deficiency in T cells leads to increased expression of Th2 effector cytokines in vitro and in vivo and Grail-deficient mice are more susceptible to allergic asthma. Mechanistically, the enhanced effector function of Grail-deficient Th2 cells is mediated by increased expression of Stat6 and IL-4 receptor α-chain. Grail interacts with Stat6 and targets it for ubiquitination and degradation. Thus, our results indicate that Grail plays a critical role in controlling Th2 development through a negative feedback loop.
authors.affiliation: Department of Immunology, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Anupama
authors.initials: A
authors.lastname: Sahoo
authors.affiliation: Department of Immunology, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Alekseev
authors.affiliation: Department of Immunology, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Lidiya
authors.initials: L
authors.lastname: Obertas
authors.affiliation: Department of Immunology, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Roza
authors.initials: R
authors.lastname: Nurieva
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation; D025461:Feedback, Physiological; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4; C520250:RNF128 protein, human; D044767:Ubiquitin-Protein Ligases