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Dual roles for LUBAC signaling in thymic epithelial cell development and survival

by Strasser, Andreas , Hall, Cathrine , Bouillet, Philippe , Sheridan, Julie M. , Zhao, Kelin , Abeysekera, Waruni , Kupresanin, Fiona , Gray, Daniel H. D. , Heinlein, Melanie , Jain, Reema , Walczak, Henning , Silke, John , Rickard, James

in 13/31 / 13/95 / 14 / 14/19 / 38 / 38/91 / 692/699/249 / 692/699/255 / Adaptive immunity / AIRE protein / Animals / Apoptosis / Atrophy / Biochemistry / Biomedical and Life Sciences / Cancer / Caspase-8 / Cell activation / Cell Biology / Cell Cycle Analysis / Cell differentiation / Cell Differentiation - physiology / Cell survival / Cell Survival - physiology / Epithelial cells / Epithelial Cells - cytology / Epithelial Cells - metabolism / Flow cytometry / Immunological tolerance / Immunology / Life Sciences / Lymphocytes / Lymphocytes T / Medical research / Medulla oblongata / Mice / Mice, Inbred C57BL / Microenvironments / Mutation / Necroptosis / NF-κB protein / Proteins / Signal Transduction / Stem Cells / Thymus / Thymus Gland - cytology / Thymus Gland - metabolism / Tumor necrosis factor-TNF / Ubiquitin / Ubiquitin - metabolism / Ubiquitination

2021

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Dual roles for LUBAC signaling in thymic epithelial cell development and survival

2021

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2021

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Journal Article

Dual roles for LUBAC signaling in thymic epithelial cell development and survival

Strasser, Andreas,

Hall, Cathrine,

Bouillet, Philippe,

Sheridan, Julie M.,

Zhao, Kelin,

Abeysekera, Waruni,

Kupresanin, Fiona,

Gray, Daniel H. D.,

Heinlein, Melanie,

Jain, Reema,

Walczak, Henning,

Silke, John,

Rickard, James

2021

Overview

Thymic epithelial cells (TECs) form a unique microenvironment that orchestrates T cell differentiation and immunological tolerance. Despite the importance of TECs for adaptive immunity, there is an incomplete understanding of the signalling networks that support their differentiation and survival. We report that the linear ubiquitin chain assembly complex (LUBAC) is essential for medullary TEC (mTEC) differentiation, cortical TEC survival and prevention of premature thymic atrophy. TEC-specific loss of LUBAC proteins, HOIL-1 or HOIP, severely impaired expansion of the thymic medulla and AIRE-expressing cells. Furthermore, HOIL-1-deficiency caused early thymic atrophy due to Caspase-8/MLKL-dependent apoptosis/necroptosis of cortical TECs. By contrast, deficiency in the LUBAC component, SHARPIN, caused relatively mild defects only in mTECs. These distinct roles for LUBAC components in TECs correlate with their function in linear ubiquitination, NFκB activation and cell survival. Thus, our findings reveal dual roles for LUBAC signaling in TEC differentiation and survival.

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Publisher

Nature Publishing Group UK,Nature Publishing Group

Subject

13/31

/ 13/95

/ 14

/ 14/19

/ 38

/ 38/91

/ 692/699/249