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LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation
The linear ubiquitin chain assembly complex (LUBAC), consisting of SHANK-associated RH-domain–interacting protein (SHARPIN), heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1), and HOIL-1–interacting protein (HOIP), is a critical regulator of inflammation and immunity. This is highlighted by the fact th...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110014/ https://www.ncbi.nlm.nih.gov/pubmed/27810922 http://dx.doi.org/10.1084/jem.20160041 |
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author | Zinngrebe, Julia Rieser, Eva Taraborrelli, Lucia Peltzer, Nieves Hartwig, Torsten Ren, Hongwei Kovács, Ildikó Endres, Cornelia Draber, Peter Darding, Maurice von Karstedt, Silvia Lemke, Johannes Dome, Balazs Bergmann, Michael Ferguson, Brian J. Walczak, Henning |
author_facet | Zinngrebe, Julia Rieser, Eva Taraborrelli, Lucia Peltzer, Nieves Hartwig, Torsten Ren, Hongwei Kovács, Ildikó Endres, Cornelia Draber, Peter Darding, Maurice von Karstedt, Silvia Lemke, Johannes Dome, Balazs Bergmann, Michael Ferguson, Brian J. Walczak, Henning |
author_sort | Zinngrebe, Julia |
collection | PubMed |
description | The linear ubiquitin chain assembly complex (LUBAC), consisting of SHANK-associated RH-domain–interacting protein (SHARPIN), heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1), and HOIL-1–interacting protein (HOIP), is a critical regulator of inflammation and immunity. This is highlighted by the fact that patients with perturbed linear ubiquitination caused by mutations in the Hoip or Hoil-1 genes, resulting in knockouts of these proteins, may simultaneously suffer from immunodeficiency and autoinflammation. TLR3 plays a crucial, albeit controversial, role in viral infection and tissue damage. We identify a pivotal role of LUBAC in TLR3 signaling and discover a functional interaction between LUBAC components and TLR3 as crucial for immunity to influenza A virus infection. On the biochemical level, we identify LUBAC components as interacting with the TLR3-signaling complex (SC), thereby enabling TLR3-mediated gene activation. Absence of LUBAC components increases formation of a previously unrecognized TLR3-induced death-inducing SC, leading to enhanced cell death. Intriguingly, excessive TLR3-mediated cell death, induced by double-stranded RNA present in the skin of SHARPIN-deficient chronic proliferative dermatitis mice (cpdm), is a major contributor to their autoinflammatory skin phenotype, as genetic coablation of Tlr3 substantially ameliorated cpdm dermatitis. Thus, LUBAC components control TLR3-mediated innate immunity, thereby preventing development of immunodeficiency and autoinflammation. |
format | Online Article Text |
id | pubmed-5110014 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-51100142017-05-14 LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation Zinngrebe, Julia Rieser, Eva Taraborrelli, Lucia Peltzer, Nieves Hartwig, Torsten Ren, Hongwei Kovács, Ildikó Endres, Cornelia Draber, Peter Darding, Maurice von Karstedt, Silvia Lemke, Johannes Dome, Balazs Bergmann, Michael Ferguson, Brian J. Walczak, Henning J Exp Med Research Articles The linear ubiquitin chain assembly complex (LUBAC), consisting of SHANK-associated RH-domain–interacting protein (SHARPIN), heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1), and HOIL-1–interacting protein (HOIP), is a critical regulator of inflammation and immunity. This is highlighted by the fact that patients with perturbed linear ubiquitination caused by mutations in the Hoip or Hoil-1 genes, resulting in knockouts of these proteins, may simultaneously suffer from immunodeficiency and autoinflammation. TLR3 plays a crucial, albeit controversial, role in viral infection and tissue damage. We identify a pivotal role of LUBAC in TLR3 signaling and discover a functional interaction between LUBAC components and TLR3 as crucial for immunity to influenza A virus infection. On the biochemical level, we identify LUBAC components as interacting with the TLR3-signaling complex (SC), thereby enabling TLR3-mediated gene activation. Absence of LUBAC components increases formation of a previously unrecognized TLR3-induced death-inducing SC, leading to enhanced cell death. Intriguingly, excessive TLR3-mediated cell death, induced by double-stranded RNA present in the skin of SHARPIN-deficient chronic proliferative dermatitis mice (cpdm), is a major contributor to their autoinflammatory skin phenotype, as genetic coablation of Tlr3 substantially ameliorated cpdm dermatitis. Thus, LUBAC components control TLR3-mediated innate immunity, thereby preventing development of immunodeficiency and autoinflammation. The Rockefeller University Press 2016-11-14 /pmc/articles/PMC5110014/ /pubmed/27810922 http://dx.doi.org/10.1084/jem.20160041 Text en © 2016 Zinngrebe et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Research Articles Zinngrebe, Julia Rieser, Eva Taraborrelli, Lucia Peltzer, Nieves Hartwig, Torsten Ren, Hongwei Kovács, Ildikó Endres, Cornelia Draber, Peter Darding, Maurice von Karstedt, Silvia Lemke, Johannes Dome, Balazs Bergmann, Michael Ferguson, Brian J. Walczak, Henning LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation |
title | LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation |
title_full | LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation |
title_fullStr | LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation |
title_full_unstemmed | LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation |
title_short | LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation |
title_sort | lubac deficiency perturbs tlr3 signaling to cause immunodeficiency and autoinflammation |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110014/ https://www.ncbi.nlm.nih.gov/pubmed/27810922 http://dx.doi.org/10.1084/jem.20160041 |
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