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TNFR1-d2 carrying the p.(Thr79Met) pathogenic variant is a potential novel actor of TNFα/TNFR1 signalling regulation in the pathophysiology of TRAPS
Binding of tumour necrosis factor α (TNFα) to its receptor (TNFR1) is critical for both survival and death cellular pathways. TNFα/TNFR1 signalling is complex and tightly regulated at different levels to control cell fate decisions. Previously, we identified TNFR1-d2, an exon 2-spliced transcript of...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893027/ https://www.ncbi.nlm.nih.gov/pubmed/33603056 http://dx.doi.org/10.1038/s41598-021-83539-9 |
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author | Rittore, Cécile Méchin, Déborah Sanchez, Elodie Marinèche, Léa Ea, Vuthy Soler, Stephan Vereecke, Marion Mallavialle, Aude Richard, Eric Duroux-Richard, Isabelle Apparailly, Florence Touitou, Isabelle Grandemange, Sylvie |
author_facet | Rittore, Cécile Méchin, Déborah Sanchez, Elodie Marinèche, Léa Ea, Vuthy Soler, Stephan Vereecke, Marion Mallavialle, Aude Richard, Eric Duroux-Richard, Isabelle Apparailly, Florence Touitou, Isabelle Grandemange, Sylvie |
author_sort | Rittore, Cécile |
collection | PubMed |
description | Binding of tumour necrosis factor α (TNFα) to its receptor (TNFR1) is critical for both survival and death cellular pathways. TNFα/TNFR1 signalling is complex and tightly regulated at different levels to control cell fate decisions. Previously, we identified TNFR1-d2, an exon 2-spliced transcript of TNFRSF1A gene encoding TNFR1, whose splicing may be modulated by polymorphisms associated with inflammatory disorders. Here, we investigated the impact of TNFRSF1A variants involved in TNFR-associated periodic syndrome (TRAPS) on TNFR1-d2 protein expression and activity. We found that TNFR1-d2 could be translated by using an internal translation initiation codon and a de novo internal ribosome entry site (IRES), which resulted in a putative TNFR1 isoform lacking its N-terminal region. The kinetic of assembly of TNFR1-d2 clusters at the cell surface was reduced as compared with full-length TNFR1. Although co-localized with the full-length TNFR1, TNFR1-d2 neither activated nuclear factor (NF)-κB signalling, nor interfered with TNFR1-induced NF-κB activation. Translation of TNFR1-d2 carrying the severe p.(Thr79Met) pathogenic variant (also known as T50M) was initiated at the mutated codon, resulting in an elongated extracellular domain, increased speed to form preassembled clusters in absence of TNFα, and constitutive NF-κB activation. Overall, TNFR1-d2 might reflect the complexity of the TNFR1 signalling pathways and could be involved in TRAPS pathophysiology of patients carrying the p.(Thr79Met) disease-causing variant. |
format | Online Article Text |
id | pubmed-7893027 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78930272021-02-23 TNFR1-d2 carrying the p.(Thr79Met) pathogenic variant is a potential novel actor of TNFα/TNFR1 signalling regulation in the pathophysiology of TRAPS Rittore, Cécile Méchin, Déborah Sanchez, Elodie Marinèche, Léa Ea, Vuthy Soler, Stephan Vereecke, Marion Mallavialle, Aude Richard, Eric Duroux-Richard, Isabelle Apparailly, Florence Touitou, Isabelle Grandemange, Sylvie Sci Rep Article Binding of tumour necrosis factor α (TNFα) to its receptor (TNFR1) is critical for both survival and death cellular pathways. TNFα/TNFR1 signalling is complex and tightly regulated at different levels to control cell fate decisions. Previously, we identified TNFR1-d2, an exon 2-spliced transcript of TNFRSF1A gene encoding TNFR1, whose splicing may be modulated by polymorphisms associated with inflammatory disorders. Here, we investigated the impact of TNFRSF1A variants involved in TNFR-associated periodic syndrome (TRAPS) on TNFR1-d2 protein expression and activity. We found that TNFR1-d2 could be translated by using an internal translation initiation codon and a de novo internal ribosome entry site (IRES), which resulted in a putative TNFR1 isoform lacking its N-terminal region. The kinetic of assembly of TNFR1-d2 clusters at the cell surface was reduced as compared with full-length TNFR1. Although co-localized with the full-length TNFR1, TNFR1-d2 neither activated nuclear factor (NF)-κB signalling, nor interfered with TNFR1-induced NF-κB activation. Translation of TNFR1-d2 carrying the severe p.(Thr79Met) pathogenic variant (also known as T50M) was initiated at the mutated codon, resulting in an elongated extracellular domain, increased speed to form preassembled clusters in absence of TNFα, and constitutive NF-κB activation. Overall, TNFR1-d2 might reflect the complexity of the TNFR1 signalling pathways and could be involved in TRAPS pathophysiology of patients carrying the p.(Thr79Met) disease-causing variant. Nature Publishing Group UK 2021-02-18 /pmc/articles/PMC7893027/ /pubmed/33603056 http://dx.doi.org/10.1038/s41598-021-83539-9 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Rittore, Cécile Méchin, Déborah Sanchez, Elodie Marinèche, Léa Ea, Vuthy Soler, Stephan Vereecke, Marion Mallavialle, Aude Richard, Eric Duroux-Richard, Isabelle Apparailly, Florence Touitou, Isabelle Grandemange, Sylvie TNFR1-d2 carrying the p.(Thr79Met) pathogenic variant is a potential novel actor of TNFα/TNFR1 signalling regulation in the pathophysiology of TRAPS |
title | TNFR1-d2 carrying the p.(Thr79Met) pathogenic variant is a potential novel actor of TNFα/TNFR1 signalling regulation in the pathophysiology of TRAPS |
title_full | TNFR1-d2 carrying the p.(Thr79Met) pathogenic variant is a potential novel actor of TNFα/TNFR1 signalling regulation in the pathophysiology of TRAPS |
title_fullStr | TNFR1-d2 carrying the p.(Thr79Met) pathogenic variant is a potential novel actor of TNFα/TNFR1 signalling regulation in the pathophysiology of TRAPS |
title_full_unstemmed | TNFR1-d2 carrying the p.(Thr79Met) pathogenic variant is a potential novel actor of TNFα/TNFR1 signalling regulation in the pathophysiology of TRAPS |
title_short | TNFR1-d2 carrying the p.(Thr79Met) pathogenic variant is a potential novel actor of TNFα/TNFR1 signalling regulation in the pathophysiology of TRAPS |
title_sort | tnfr1-d2 carrying the p.(thr79met) pathogenic variant is a potential novel actor of tnfα/tnfr1 signalling regulation in the pathophysiology of traps |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893027/ https://www.ncbi.nlm.nih.gov/pubmed/33603056 http://dx.doi.org/10.1038/s41598-021-83539-9 |
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