title: Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis.
abstract: The linear ubiquitin chain assembly complex (LUBAC) is essential for innate immunity in mice and humans, yet its role in adaptive immunity is unclear. Here we show that the LUBAC components HOIP, HOIL-1 and SHARPIN have essential roles in late thymocyte differentiation, FOXP3+regulatory T (Treg)-cell development and Treg cell homeostasis. LUBAC activity is not required to prevent TNF-induced apoptosis or necroptosis but is necessary for the transcriptional programme of the penultimate stage of thymocyte differentiation. Treg cell-specific ablation of HOIP causes severe Treg cell deficiency and lethal immune pathology, revealing an ongoing requirement of LUBAC activity for Treg cell homeostasis. These data reveal stage-specific requirements for LUBAC in coordinating the signals required for T-cell differentiation.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.|Department of Medical Biology, The University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Charis E
authors.initials: CE
authors.lastname: Teh
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.|Department of Medical Biology, The University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Najoua
authors.identifier: 0000-0002-0165-3324
authors.initials: N
authors.lastname: Lalaoui
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.|Department of Medical Biology, The University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Reema
authors.initials: R
authors.lastname: Jain
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.|Department of Medical Biology, The University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Antonia N
authors.initials: AN
authors.lastname: Policheni
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.|Department of Medical Biology, The University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Heinlein
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.|Department of Medical Biology, The University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Silvia
authors.initials: S
authors.lastname: Alvarez-Diaz
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.|Department of Medical Biology, The University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Sheridan
authors.affiliation: Centre for Cell Death, Cancer and Inflammation, University College London, London WC1E 6BT, UK.
authors.forename: Eva
authors.initials: E
authors.lastname: Rieser
authors.affiliation: Centre for Cell Death, Cancer and Inflammation, University College London, London WC1E 6BT, UK.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Deuser
authors.affiliation: Centre for Cell Death, Cancer and Inflammation, University College London, London WC1E 6BT, UK.
authors.forename: Maurice
authors.initials: M
authors.lastname: Darding
authors.affiliation: The Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, 792 Elizabeth Street, Melbourne, Victoria 3000, Australia.|The Australian Research Council Centre of Excellence for Advanced Molecular Imaging, The University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Hui-Fern
authors.initials: HF
authors.lastname: Koay
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Fiona
authors.initials: F
authors.lastname: Kupresanin
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.|Department of Medical Biology, The University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: O'Reilly
authors.affiliation: The Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, 792 Elizabeth Street, Melbourne, Victoria 3000, Australia.|The Australian Research Council Centre of Excellence for Advanced Molecular Imaging, The University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Dale I
authors.identifier: 0000-0002-3009-5472
authors.initials: DI
authors.lastname: Godfrey
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.|Department of Mathematics and Statistics, The University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Gordon K
authors.identifier: 0000-0001-9221-2892
authors.initials: GK
authors.lastname: Smyth
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.|Department of Medical Biology, The University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.|Department of Medical Biology, The University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.affiliation: Centre for Cell Death, Cancer and Inflammation, University College London, London WC1E 6BT, UK.
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.|Department of Medical Biology, The University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: John
authors.identifier: 0000-0002-7611-5774
authors.initials: J
authors.lastname: Silke
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.|Department of Medical Biology, The University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Daniel H D
authors.initials: DH
authors.lastname: Gray
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D019295:Computational Biology; D005786:Gene Expression Regulation / Q000502:physiology; D005838:Genotype; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D012313:RNA / Q000235:genetics; D017423:Sequence Analysis, RNA; D013601:T-Lymphocytes / Q000145:classification / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology*; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D025801:Ubiquitin; D012313:RNA; D044767:Ubiquitin-Protein Ligases