title: Cbl-b mediates TGFβ sensitivity by downregulating inhibitory SMAD7 in primary T cells.
abstract: T cell-intrinsic transforming growth factor β (TGFβ) receptor signaling plays an essential role in controlling immune responses. The RING-type E3 ligase Cbl-b has been shown to mediate the sensitivity of T cells to TGFβ; however, the mechanism underlying this process is unknown. This study shows that SMAD7, an established negative regulator of TGFβ receptor (TGFβR) signaling, is a key downstream effector target of Cbl-b. SMAD7 protein levels, but not SMAD7 mRNA levels, are upregulated in cblb(-/-) T cells. Cbl-b directly interacts with and ubiquitinates SMAD7, suggesting that Cbl-b posttranscriptionally regulates SMAD7. In support of this notion, concomitant genetic loss of SMAD7 in cblb(-/-) mice restored TGFβ sensitivity on T cell cytokine responses and abrogated the tumor rejection phenotype of cblb(-/-) mice. These results demonstrate an essential and non-redundant role for Cbl-b in controlling TGFβR signaling by directly targeting SMAD7 for degradation during T cell responses in vitro and in vivo.
authors.affiliation: Department for Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gruber
authors.forename: Reinhard
authors.initials: R
authors.lastname: Hinterleitner
authors.forename: Natascha
authors.initials: N
authors.lastname: Hermann-Kleiter
authors.forename: Marlies
authors.initials: M
authors.lastname: Meisel
authors.forename: Ingo
authors.initials: I
authors.lastname: Kleiter
authors.forename: Chiuhui Mary
authors.initials: CM
authors.lastname: Wang
authors.forename: Antonella
authors.initials: A
authors.lastname: Viola
authors.forename: Christa
authors.initials: C
authors.lastname: Pfeifhofer-Obermair
authors.forename: Gottfried
authors.initials: G
authors.lastname: Baier
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000098815:T-bet Transcription Factor
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; D051906:Smad7 Protein; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; D050721:Proto-Oncogene Proteins c-cbl
keywords: Cbl-b; SMAD; TGFβ signaling