title: CARMA1 controls Th2 cell-specific cytokine expression through regulating JunB and GATA3 transcription factors.
abstract: The scaffold protein CARMA1 is required for the TCR-induced lymphocyte activation. In this study, we show that CARMA1 also plays an essential role in T cell differentiation. We have found that the adoptive transfer of bone marrow cells expressing constitutively active CARMA1 results in lung inflammation, eosinophilia, and elevated levels of IL-4, IL-5, and IL-10 in recipient mice. In contrast, CARMA1-deficient T cells are defective in TCR-induced expression of Th2 cytokines, suggesting that CARMA1 preferentially directs Th2 differentiation. The impaired cytokine production is due to reduced expression of JunB and GATA3 transcription factors. CARMA1 deficiency affects JunB stability resulting in its enhanced ubiquitination and degradation. In contrast, TCR-dependent induction of GATA3 is suppressed at the transcriptional level. We also found that supplementation with IL-4 partially restored GATA3 expression in CARMA1-deficient CD4(+) splenocytes and subsequently production of GATA3-dependent cytokines IL-5 and IL-13. Therefore, our work provides the mechanism by which CARMA1 regulates Th2 cell differentiation.
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Marzenna
authors.initials: M
authors.lastname: Blonska
authors.forename: Donghyun
authors.initials: D
authors.lastname: Joo
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Zweidler-McKay
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Zhao
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
mesh_terms: D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050990:GATA3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000633:toxicity; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis* / Q000235:genetics; D011657:Pulmonary Eosinophilia / Q000235:genetics; D011828:Radiation Chimera; D011993:Recombinant Fusion Proteins / Q000502:physiology; D017384:Sequence Deletion; D013047:Specific Pathogen-Free Organisms; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
chemical_list: D053468:CARD Signaling Adaptor Proteins; C430880:CARD10 protein, human; C496467:Card11 protein, mouse; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C494748:Gata3 protein, mouse; D007378:Interleukins; D016755:Proto-Oncogene Proteins c-jun; D011993:Recombinant Fusion Proteins; D015847:Interleukin-4; D010047:Ovalbumin