Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis

Charis E Teh; Najoua Lalaoui; Reema Jain; Antonia N Policheni; Melanie Heinlein; Silvia Alvarez-Diaz; Julie M Sheridan; Eva Rieser; Stefanie Deuser; Maurice Darding; Hui-Fern Koay; Yifang Hu; Fiona Kupresanin; Lorraine A O'Reilly; Dale I Godfrey; Gordon K Smyth; Philippe Bouillet; Andreas Strasser; Henning Walczak; John Silke; Daniel H D Gray

doi:10.1038/ncomms13353

Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis

Nat Commun. 2016 Nov 18:7:13353. doi: 10.1038/ncomms13353.

Authors

Charis E Teh^{1

2}, Najoua Lalaoui^{1

2}, Reema Jain^{1

2}, Antonia N Policheni^{1

2}, Melanie Heinlein^{1

2}, Silvia Alvarez-Diaz^{1

2}, Julie M Sheridan^{1

2}, Eva Rieser³, Stefanie Deuser³, Maurice Darding³, Hui-Fern Koay^{4

5}, Yifang Hu¹, Fiona Kupresanin¹, Lorraine A O'Reilly^{1

2}, Dale I Godfrey^{4

5}, Gordon K Smyth^{1

6}, Philippe Bouillet^{1

2}, Andreas Strasser^{1

2}, Henning Walczak³, John Silke^{1

2}, Daniel H D Gray^{1

2}

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
² Department of Medical Biology, The University of Melbourne, Melbourne, Victoria 3052, Australia.
³ Centre for Cell Death, Cancer and Inflammation, University College London, London WC1E 6BT, UK.
⁴ 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.
⁵ The Australian Research Council Centre of Excellence for Advanced Molecular Imaging, The University of Melbourne, Melbourne, Victoria 3052, Australia.
⁶ Department of Mathematics and Statistics, The University of Melbourne, Melbourne, Victoria 3052, Australia.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Cell Differentiation / physiology*
Cells, Cultured
Computational Biology
Gene Expression Regulation / physiology
Genotype
Homeostasis / physiology*
Mice
Protein Multimerization
Protein Processing, Post-Translational
RNA / genetics
Sequence Analysis, RNA
T-Lymphocytes / classification
T-Lymphocytes / physiology*
Thymus Gland / cytology*
Ubiquitin / chemistry
Ubiquitin / metabolism*
Ubiquitin-Protein Ligases / metabolism
Ubiquitination

Substances

Ubiquitin
RNA
Ubiquitin-Protein Ligases

Abstract

Publication types

MeSH terms

Substances

Grants and funding