title: The ubiquitin ligase Peli1 negatively regulates T cell activation and prevents autoimmunity.
abstract: T cell activation is subject to tight regulation to avoid inappropriate responses to self antigens. Here we show that genetic deficiency in the ubiquitin ligase Peli1 caused hyperactivation of T cells and rendered T cells refractory to suppression by regulatory T cells and transforming growth factor-β (TGF-β). As a result, Peli1-deficient mice spontaneously developed autoimmunity characterized by multiorgan inflammation and autoantibody production. Peli1 deficiency resulted in the nuclear accumulation of c-Rel, a member of the NF-κB family of transcription factors with pivotal roles in T cell activation. Peli1 negatively regulated c-Rel by mediating its Lys48 (K48) ubiquitination. Our results identify Peli1 as a critical factor in the maintenance of peripheral T cell tolerance and demonstrate a previously unknown mechanism of c-Rel regulation.
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Mikyoung
authors.initials: M
authors.lastname: Chang
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Chang
authors.forename: Yichuan
authors.initials: Y
authors.lastname: Xiao
authors.forename: George C
authors.initials: GC
authors.lastname: Brittain
authors.forename: Jiayi
authors.initials: J
authors.lastname: Yu
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhou
authors.forename: Yi-Hong
authors.initials: YH
authors.lastname: Wang
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cheng
authors.forename: Pingwei
authors.initials: P
authors.lastname: Li
authors.forename: Brian A
authors.initials: BA
authors.lastname: Rabinovich
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
mesh_terms: D000818:Animals; D015551:Autoimmunity; D018106:CD28 Antigens / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000502:physiology*; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination
chemical_list: D018106:CD28 Antigens; D016328:NF-kappa B; D009687:Nuclear Proteins; D020569:Proto-Oncogene Proteins c-rel; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D044767:Ubiquitin-Protein Ligases; C418046:Peli1 protein, mouse