Cargando…

NF-κB Pathway in Autoinflammatory Diseases: Dysregulation of Protein Modifications by Ubiquitin Defines a New Category of Autoinflammatory Diseases

Autoinflammatory diseases are caused by defects in genes that regulate the innate immunity. Recently, the scope of autoinflammation has been broadened to include diseases that result from dysregulations in protein modifications by the highly conserved ubiquitin (Ub) peptides. Thus far these diseases...

Descripción completa

Detalles Bibliográficos
Autores principales: Aksentijevich, Ivona, Zhou, Qing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395695/
https://www.ncbi.nlm.nih.gov/pubmed/28469620
http://dx.doi.org/10.3389/fimmu.2017.00399
_version_ 1783229921407008768
author Aksentijevich, Ivona
Zhou, Qing
author_facet Aksentijevich, Ivona
Zhou, Qing
author_sort Aksentijevich, Ivona
collection PubMed
description Autoinflammatory diseases are caused by defects in genes that regulate the innate immunity. Recently, the scope of autoinflammation has been broadened to include diseases that result from dysregulations in protein modifications by the highly conserved ubiquitin (Ub) peptides. Thus far these diseases consist of linear ubiquitin chain assembly complex (LUBAC) and OTULIN deficiencies, and haploinsufficiency of A20. The LUBAC is critical for linear ubiquitination of key signaling molecules in immune response pathways, while deubiquitinase enzymes, OTULIN and TNFAIP3/A20, reverse the effects of ubiquitination by hydrolyzing linear (Met1) and Lys63 (K63) Ub moieties, respectively, from conjugated proteins. Consequently, OTULIN or A20-deficient cells have an excess of Met1 or K63 Ub chains on NEMO, RIPK1, and other target substrates, which lead to constitutive activation of the NF-kB pathway. Mutant cells produce elevated levels of many proinflammatory cytokines and respond to therapy with cytokine inhibitors. Patients with an impairment in LUBAC stability have compromised NF-kB responses in non-immune cells such as fibroblasts, while their monocytes are hyperresponsive to IL-1β. Discoveries of germline mutations in enzymes that regulate protein modifications by Ub define a new category of autoinflammatory diseases caused by upregulations in the NF-kB signaling. The primary aim of this review is to summarize the latest developments in our understanding of the etiology of autoinflammation.
format Online
Article
Text
id pubmed-5395695
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-53956952017-05-03 NF-κB Pathway in Autoinflammatory Diseases: Dysregulation of Protein Modifications by Ubiquitin Defines a New Category of Autoinflammatory Diseases Aksentijevich, Ivona Zhou, Qing Front Immunol Immunology Autoinflammatory diseases are caused by defects in genes that regulate the innate immunity. Recently, the scope of autoinflammation has been broadened to include diseases that result from dysregulations in protein modifications by the highly conserved ubiquitin (Ub) peptides. Thus far these diseases consist of linear ubiquitin chain assembly complex (LUBAC) and OTULIN deficiencies, and haploinsufficiency of A20. The LUBAC is critical for linear ubiquitination of key signaling molecules in immune response pathways, while deubiquitinase enzymes, OTULIN and TNFAIP3/A20, reverse the effects of ubiquitination by hydrolyzing linear (Met1) and Lys63 (K63) Ub moieties, respectively, from conjugated proteins. Consequently, OTULIN or A20-deficient cells have an excess of Met1 or K63 Ub chains on NEMO, RIPK1, and other target substrates, which lead to constitutive activation of the NF-kB pathway. Mutant cells produce elevated levels of many proinflammatory cytokines and respond to therapy with cytokine inhibitors. Patients with an impairment in LUBAC stability have compromised NF-kB responses in non-immune cells such as fibroblasts, while their monocytes are hyperresponsive to IL-1β. Discoveries of germline mutations in enzymes that regulate protein modifications by Ub define a new category of autoinflammatory diseases caused by upregulations in the NF-kB signaling. The primary aim of this review is to summarize the latest developments in our understanding of the etiology of autoinflammation. Frontiers Media S.A. 2017-04-19 /pmc/articles/PMC5395695/ /pubmed/28469620 http://dx.doi.org/10.3389/fimmu.2017.00399 Text en Copyright © 2017 Aksentijevich and Zhou. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Aksentijevich, Ivona
Zhou, Qing
NF-κB Pathway in Autoinflammatory Diseases: Dysregulation of Protein Modifications by Ubiquitin Defines a New Category of Autoinflammatory Diseases
title NF-κB Pathway in Autoinflammatory Diseases: Dysregulation of Protein Modifications by Ubiquitin Defines a New Category of Autoinflammatory Diseases
title_full NF-κB Pathway in Autoinflammatory Diseases: Dysregulation of Protein Modifications by Ubiquitin Defines a New Category of Autoinflammatory Diseases
title_fullStr NF-κB Pathway in Autoinflammatory Diseases: Dysregulation of Protein Modifications by Ubiquitin Defines a New Category of Autoinflammatory Diseases
title_full_unstemmed NF-κB Pathway in Autoinflammatory Diseases: Dysregulation of Protein Modifications by Ubiquitin Defines a New Category of Autoinflammatory Diseases
title_short NF-κB Pathway in Autoinflammatory Diseases: Dysregulation of Protein Modifications by Ubiquitin Defines a New Category of Autoinflammatory Diseases
title_sort nf-κb pathway in autoinflammatory diseases: dysregulation of protein modifications by ubiquitin defines a new category of autoinflammatory diseases
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395695/
https://www.ncbi.nlm.nih.gov/pubmed/28469620
http://dx.doi.org/10.3389/fimmu.2017.00399
work_keys_str_mv AT aksentijevichivona nfkbpathwayinautoinflammatorydiseasesdysregulationofproteinmodificationsbyubiquitindefinesanewcategoryofautoinflammatorydiseases
AT zhouqing nfkbpathwayinautoinflammatorydiseasesdysregulationofproteinmodificationsbyubiquitindefinesanewcategoryofautoinflammatorydiseases