title: Members of the novel UBASH3/STS/TULA family of cellular regulators suppress T-cell-driven inflammatory responses in vivo.
abstract: The UBASH3/STS/TULA family consists of two members sharing substantial homology and a similar multi-domain architecture, which includes a C-terminal histidine phosphatase domain capable of dephosphorylating phosphotyrosine-containing substrates. TULA-family proteins act as downregulators of receptor-induced activation in several cell types, including T cells and platelets. Deletion of both family members in mice has been shown to result in hyperresponsiveness of T cells to T-cell receptor (TCR)/CD3 complex engagement, but little is known about the biological consequences of double knockout (dKO) and especially of either single KO (sKO). We elucidated the biological consequences of the lack of TULA-family proteins in dKO and TULA and TULA-2 sKO animals. In order to do so, we examined immune responses in Trinitrobenzene sulfonic acid (TNBS)-induced colitis, a mouse model of human inflammatory bowel disease, which is characterized by the involvement of multiple cell types, of which T cells have a crucial role, in the development of a pathological inflammatory condition. Our data indicate that TNBS treatment upregulates T-cell responses in all KO mice studied to a significantly higher degree than in wild-type mice. Although the lack of either TULA-family member exacerbates inflammation and T-cell responses in a specific fashion, the lack of both TULA and TULA-2 in dKO exerts a higher effect than the lack of a single family member in TULA and TULA-2 sKO. Analysis of T-cell responses and TCR-mediated signaling argues that the proteins investigated affect T-cell signaling by regulating phosphorylation of Zap-70, a key protein tyrosine kinase.
authors.affiliation: Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Tiffanny N
authors.initials: TN
authors.lastname: Newman
authors.affiliation: Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Liverani
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Elitza
authors.initials: E
authors.lastname: Ivanova
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Gian L
authors.initials: GL
authors.lastname: Russo
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Carpino
authors.affiliation: 1] Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, USA [2] Autoimmunity Center, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Doina
authors.initials: D
authors.lastname: Ganea
authors.affiliation: 1] Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA, USA [2] Department of Anatomy and Neurobiology, Northeast Ohio Medical University, Rootstown, OH, USA.
authors.forename: Fayez
authors.initials: F
authors.lastname: Safadi
authors.affiliation: 1] Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, USA [2] Department of Physiology, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Satya P
authors.initials: SP
authors.lastname: Kunapuli
authors.affiliation: 1] Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA, USA [2] Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, USA [3] Autoimmunity Center, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Tsygankov
mesh_terms: D000818:Animals; D003092:Colitis / Q000276:immunology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D011948:Receptors, Antigen, T-Cell; C482177:Sts-2 protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D017027:Protein Tyrosine Phosphatases; C553497:TULA-2 protein, mouse